Interferon-alpha induced genes

ABSTRACT

The present disclosure relates to identification of genes upregulated by interferon-α administration, in particular the human genes corresponding to the cDNA sequences in GenBank designated g4586459, g2342476, g3327161 and g4529886. Determination of expression products of these genes is proposed as having utility in predicting responsiveness to treatment with interferon-α and other interferons which act at the Type 1 interferon receptor. Therapeutic use of the proteins encoded by the same genes is also envisaged.

FIELD OF THE INVENTION

[0001] The present invention relates to identification of genesupregulated by interferon-α (IFN-α) administration. Detection ofexpression products of these genes may thus find use in predictingresponsiveness to IFN-α and other interferons which act at the Type 1interferon receptor. Therapeutic use of the proteins encoded by the samegenes is also envisaged.

BACKGROUND OF THE INVENTION

[0002] IFN-α is widely used for the treatment of a number of disorders.Disorders which may be treated using IFN-α include neoplastic diseasessuch as leukemia, lymphomas, and solid tumours, AIDS-related Kaposi'ssarcoma and viral infections such as chronic hepatitis. IFN-α has alsobeen proposed for administration via the oromucosal route for thetreatment of autoimmune, mycobacterial, neurodegenerative, parasitic andviral disease. In particular, IFN-α has been proposed, for example, forthe treatment of multiple sclerosis, leprosy, tuberculosis,encephalitis, malaria, cervical cancer, genital herpes, hepatitis B andC, HIV, HPV and HSV-1 and 2. It has also been suggested for thetreatment of arthritis, lupus and diabetes. Neoplastic diseases such asmultiple myeloma, hairy cell leukemia, chronic myelogenous leukemia, lowgrade lymphoma, cutaneous T-cell lymphoma, carcinoid tumours, cervicalcancer, sarcomas including Kaposi's sarcoma, kidney tumours, carcinomasincluding renal cell carcinoma, hepatic cellular carcinoma,nasopharyngeal carcinoma, haematological malignancies, colorectalcancer, glioblastoma, laryngeal papillomas, lung cancer, colon cancer,malignant melanoma and brain tumours are also suggested as beingtreatable by administration of IFN-via the oromucosal route, i.e. theoral route or the nasal route.

[0003] IFN-α is a member of the Type 1 interferon family, which exerttheir characteristic biological activities through interaction with theType 1 interferon receptor. Other Type 1 interferons include IFN-β,IFN-ω and IFN-τ.

[0004] Unfortunately, not all potential patients for treatment with aType 1 interferon such as interferon-α, particularly, for example,patients suffering from chronic viral hepatitis, neoplastic disease andrelapsing remitting multiple sclerosis, respond favourably to Type 1interferon therapy and only a fraction of those who do respond exhibitlong-term benefit. The inability of the physician to confidently predictthe therapeutic outcome of Type 1 interferon treatment raises seriousconcerns as to the cost-benefit ratio of such treatment, not only interms of wastage of an expensive biopharmaceutical and lost time intherapy, but also in terms of the serious side effects to which thepatient is exposed. Furthermore, abnormal production of IFN-α has beenshown to be associated with a number of autoimmune diseases. For thesereasons, there is much interest in identifying Type 1 interferonresponsive genes since Type 1 interferons exert their therapeutic actionby modulating the expression of a number of genes. Indeed, it is thespecific pattern of gene expression induced by Type 1 interferontreatment that determines whether a patient will respond favourably ornot to the treatment.

SUMMARY OF THE INVENTION

[0005] It has now been found that the human genes corresponding to thecDNA sequences in GenBank assigned accession nos. g4586459, g2342476,g3327161 and g4529886, correspond to a mouse gene upregulated byadministration of IFN-α by an oromucosal route or intravenously. Thesehuman genes are thus now also designated an IFN-α upregulated gene.

[0006] The proteins corresponding to GenBank cDNAs g4586459, g2342476,g3327161 and g4529886 have previously had no assigned function. Theseproteins (referred to below as HuIFRG-1, HuIFRG-2, HuIFRG-3 and HuIFRG-4proteins respectively), and functional variants thereof, are nowenvisaged as therapeutic agents, in particular for use as an anti-viral,anti-tumour or imnmunomodulatory agent. For example, they may be used inthe treatment of autoimmune, mycobacterial, neurodegenerative, parasiticor viral disease, arthritis, diabetes, lupus, multiple sclerosis,leprosy, tuberculosis, encephalitis, malaria, cervical cancer, genitalherpes, hepatitis B or C, HIV, HPV, HSV-1 or 2, or neoplastic diseasesuch as multiple myeloma, hairy cell leukemia, chronic myelogenousleukemia, low grade lymphoma, cutaneous T-cell lymphoma, carcinoidtumours, cervical cancer, sarcomas including Kaposi's sarcoma, kidneytumours, carcinomas including renal cell carcinoma, hepatic cellularcarcinoma, nasopharyngeal carcinoma, haematological malignancies,colorectal cancer, glioblastoma, laryngeal papillomas, lung cancer,colon cancer, malignant melanoma or brain tumours. In other words suchproteins may find use in treating any Type 1 interferon treatabledisease.

[0007] Determination of the level of HuIFRG-1, HuIFRG-2, HuIFRG-3 orHuIFRG-4 proteins or a naturally-occurring variant thereof, or thecorresponding mRNA, in cell samples of Type 1 interferon-treatedpatients, e.g. patients treated with IFN-α, e.g. such as by theoromucosal route or intravenously, may also be used to predictresponsiveness to such treatment. It has additionally been found thatalternatively and more preferably, such responsiveness may be judged,for example, by treating a sample of human peripheral blood mononuclearcells in vitro with a Type 1 interferon and looking for upregulation ordownregulation of an expression product, preferably mRNA, correspondingto the same gene.

[0008] According to a first aspect of the invention, there is thusprovided an isolated polypeptide comprising;

[0009] (i) the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 4, SEQ IDNO: 6 or SEQ ID NO: 8;

[0010] (ii) a variant thereof having substantially similar function,e.g. an immunomodulatory activity and/or an anti-viral activity and/oran anti-tumour activity; or

[0011] (iii) a fragment of (i) or (ii) which retains substantiallysimilar function, e.g. an immunomodulatory activity and/or an anti-viralactivity and/or an anti-tumour activity

[0012] for use in therapeutic treatment of a human or non-human animal,more particularly for use as an anti-viral, anti-tumour orimmunomodulatory agent. As indicated above, such use may extend to anyType 1 interferon treatable disease.

[0013] According to another aspect of the invention, there is providedan isolated polynucleotide, e.g. in the form of an expression vector,which directs expression in vivo of a polypeptide as defined above foruse in therapeutic treatment of a human or non-human animal, moreparticularly for use as an anti-viral, anti-tumour or immunomodulatoryagent. Such a polynucleotide will typically include a sequencecomprising:

[0014] (a) the nucleic acid of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO:5 or SEQ ID NO: 7 or the coding sequence thereof;

[0015] (b) a sequence which hybridises, e.g. under stringent conditions,to a sequence complementary to a sequence as defined in (a);

[0016] (c) a sequence that is degenerate as a result of the genetic codeto a sequence as defined in (a) or (b); or

[0017] (d) a sequence having at least 60% identity to a sequence asdefined in (a), (b) or (c);

[0018] such that the polypeptide encoded by said sequence is capable ofexpression in vivo.

[0019] In a further aspect, the invention provides a method ofpredicting responsiveness of a patient to treatment with a Type 1interferon, e.g. IFN-α treatment (such as IFN-α treatment by theoromucosal route or a parenteral route, for example, intravenously,subcutaneously or intramuscularly), which comprises determining thelevel of one or more proteins selected from the proteins defined by thesequences set forth in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQID NO: 8, and naturally-occurring variants thereof, e.g. allelicvariants, or one or more of the corresponding mRNAs, in a cell samplefrom said patient, e.g. a blood sample, wherein said sample is obtainedfrom said patient following administration of a Type 1 interferon, e.g.IFN-α by an oromucosal route or intravenously, or is treated prior tosaid determining with a Type 1 interferon such as IFN-α in vitro. Suchdetermining may be combined with determination of any other protein ormRNA whose expression is known to be affected in human cells by Type 1interferon administration e.g. IFN-α administration.

[0020] The invention also provides:

[0021] a pharmaceutical composition comprising the protein defined bythe amino acid sequence set forth in SEQ ID NO: 2, SEQ ID NO: 4, SEQ IDNO: 6 or SEQ ID NO: 8, or a functional variant thereof as defined above,and a pharmaceutically acceptable carrier or diluent:

[0022] a method of treating a subject having a Type 1 interferontreatable disease, which method comprises administering to the saidpatient an effective amount of such a protein;

[0023] use of such a protein in the manufacture of a medicament for usein therapy as an anti-viral or anti-tumour or immunomodulatory agent,more particularly for use in treatment of a Type 1 interferon treatabledisease;

[0024] a pharmaceutical composition comprising a polynucleotide asdefined above and a pharmaceutically acceptable carrier or diluent:

[0025] a method of treating a subject having a Type 1 interferontreatable disease, which method comprises administering to said patientan effective amount of such a polynucleotide;

[0026] use of such a polynucleotide in the manufacture of a medicament,e.g. a vector preparation, for use in therapy as an anti-viral,anti-tumour or immunomodulatory agent, more particularly for use intreating a Type 1 interferon treatable disease;

[0027] a polynucleotide capable of expressing in vivo an antisensesequence to a coding sequence for the amino acid sequence defined by SEQID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8, or anaturally-occurring variant of said coding sequence, for use intherapeutic treatment of a human or non-human animal and pharmaceuticalcompositions comprising such a polynucleotide in combination with apharmaceutically acceptable carrier or diluent;

[0028] an antibody to the protein defined by the amino acid sequence setforth the in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8for use in therapeutic treatment of a human or animal body andcorresponding pharmaceutical compositions.

BRIEF DESCRIPTION OF THE SEQUENCES

[0029] SEQ. ID. No. 1 is the amino acid sequence of human proteinHuIFRG-1 and its encoding cDNA.

[0030] SEQ. ID. No. 2 is the amino acid sequence alone of HuIFRG-1protein.

[0031] SEQ. ID. No. 3 is the amino acid sequence of human proteinHuIFRG-2 and its encoding cDNA.

[0032] SEQ. ID. No. 4 is the amino acid sequence alone of HuIFRG-2protein.

[0033] SEQ. ID. No. 5 is the amino acid sequence of human proteinHuIFRG-3 and its encoding cDNA.

[0034] SEQ. ID. No. 6 is the amino acid sequence alone of HuIFRG-3protein.

[0035] SEQ. ID. No. 7 is the amino acid sequence of human proteinHuIFRG-4 and its encoding cDNA.

[0036] SEQ. ID. No. 8 is the amino acid sequence alone of HuIFRG-4protein.

DETAILED DESCRIPTION OF THE INVENTION

[0037] As indicated above, human proteins HuIFRG-1, HuIFRG-2, HuIFRG-3or HuIFRG-4 and functional variants thereof are now envisaged astherapeutically useful agents, more particularly for use as ananti-viral, anti-tumour or immunomodulatory agent.

[0038] A variant of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein forthis purpose may be a naturally-occurring variant, either an allelicvariant or a species variant, which has substantially the samefunctional activity as HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 proteinand is also upregulated in response to administration of IFN-α, e.goromucosal or intravenous administration of IFN-α.

[0039] Alternatively, a variant of HuIFRG-1, HuIFRG-2, HuIFRG-3 orHuIFRG-4 protein for therapeutic use may comprise a sequence whichvaries from SEQ. ID. No. 2 but which is a non-natural mutant.

[0040] The term “functional variant” refers to a polypeptide which hasthe same essential character or basic function of HuIFRG-1, HuIFRG-2,HuIFRG-3 or HuIFRG-4 protein. The essential character of HuIFRG-1,HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein may be deemed to be as animmunomodulatory polypeptide. A functional variant polypeptide may showadditionally or alternatively anti-viral activity and/or anti-tumouractivity.

[0041] Desired anti-viral activity may, for example, be tested for asfollows. A sequence encoding a variant to be tested is cloned into aretroviral vector such as a retroviral vector derived from the Moloneymurine leukemia virus (MoMuLV) containing the viral packaging signal A,and a drug-resistance marker. A pantropic packaging cell line containingthe viral gag, and pol, genes is then co-transfected with therecombinant retroviral vector and a plasmid, pVSV-G, containing thevesicular stomatitis virus envelope glycoprotein in order to producehigh-titre infectious replication-incompetent virus (Burns et al., Proc.Natl., Acad. Sci. USA 84, 5232-5236). The infectious recombinant virusis then used to transfect interferon sensitive fibroblasts orlymphoblastoid cells and cell lines that stably express the variantprotein are then selected and tested for resistance to virus infectionin a standard interferon bio-assay (Tovey et al., Nature, 271, 622-625,1978). Growth inhibition using a standard proliferation assay (Mosmann,T., J. Immunol. Methods. 65, 55-63. 1983) and expression of MHC class Iand class II antigens using standard techniques may also be determined.

[0042] A desired functional variant of HuIFRG-1, HuIFRG-2, HuIFRG-3 orHuIFRG-4 protein may consist essentially of the sequence of SEQ ID NO:2. SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8. A functional variant ofSEQ ID NO: 2. SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8 may be apolypeptide which has a least 60% to 70% identity, preferably at least80% or at least 90% and particularly preferably at least 95%, at least97% or at least 99% identity with the amino acid sequence of SEQ ID NO:2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8 over a region of at least20, preferably at least 30, for instance at least 100 contiguous aminoacids or over the full length of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO:6 or SEQ ID NO: 8. Methods of measuring protein identity are well knownin the art.

[0043] Amino acid substitutions may be made, for example from 1, 2 or 3to 10, 20 or 30 substitutions. Conservative substitutions may be made,for example according to the following Table. Amino acids in the sameblock in the second column and preferably in the same line in the thirdcolumn may be substituted for each other. ALIPHATIC Non-polar GAP ILVPolar-uncharged CSTM NQ Polar-charged DE KR AROMATIC HFWY

[0044] Variant polypeptide sequences for therapeutic use in accordancewith the invention may be shorter polypeptide sequences, for example, apeptide of at least 20 amino acids or up to 50, 60, 70, 80, 100, 150 or200 amino acids in length is considered to fall within the scope of theinvention provided it retains appropriate biological activity ofHuIFRG-1, HuIFRG-2. HuIFRG-3 or HuIFRG-4 protein. In particular, but notexclusively, this aspect of the invention encompasses the situation whenthe variant is a fragment of a complete naturally-occurring proteinsequence.

[0045] Variant polypeptides for therapeutic use in accordance with theinvention may be chemically modified, e.g. post-translationallymodified. For example, they may be glycosylated and/or comprise modifiedamino acid residues. They may also be modified by the addition of asequence either at the N-terminus and/or C-terminus. Polypeptides fortherapeutic use in accordance with the invention may be madesynthetically or by recombinant means. Such polypeptides may be modifiedto include non-naturally occurring amino acids. e.g. D amino acids.Variant polypeptides for use in accordance with the invention may havemodifications to increase stability in vitro and/or in vivo. When thepolypeptides are produced by synthetic means, such modifications may beintroduced during production. The polypeptides may also be modifiedfollowing either synthetic or recombinant production.

[0046] A number of side chain modifications are known in the proteinmodification art and may be present in variants for therapeutic useaccording to the invention. Such modifications include, for example,modifications of amino acids by reductive alkylation by reaction with analdehyde followed by reduction with NaBH₄, amidination withmethylacetimidate or acylation with acetic anhydride.

[0047] Polypeptides for use in accordance with the invention will be insubstantially isolated form. It will be understood that the polypeptidesmay be mixed with carriers or diluents which will not interfere with theintended purpose of the polypeptide and still be regarded assubstantially isolated.

[0048] Polynucleotide Therapy

[0049] As an alternative to administration of HuIFRG-1, HuIFRG-2,HuIFRG-3 or HuIFRG-4 protein, or a functional variant thereof asdescribed above, an isolated polynucleotide may be administered, e.g. inthe form of an expression vector such as a viral vector, which directsexpression of the desired polypeptide in vivo. Hence, as indicatedabove, in a further embodiment the invention provides an isolatedpolynucleotide, which directs expression in vivo of a polypeptide asdefined above, which polynucleotide includes a sequence comprising:

[0050] (a) the nucleic acid of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO:5 or SEQ ID NO: 7 or the coding sequence thereof;

[0051] (b) a sequence which hybridises, e.g under stringent conditions,to a sequence complementary to a sequence as defined in (a);

[0052] (c) a sequence that is degenerate as a result of the genetic codeto a sequence as defined in (a) or (b); or

[0053] (e) a sequence having at least 60% identity to a sequence asdefined in (a), (b) or (c)

[0054] for use in therapeutic treatment of a human or non-human animal,more particularly for use as an anti-viral, anti-tumour orimnmunomodulatory agent.

[0055] Preferably, such a polynucleotide will be a DNA. The codingsequence for HuIFRG-1, HuIFRG-2. HuIFRG-3 or HuIFRG-4 protein or avariant thereof may be provided by a cDNA sequence or a genomic DNAsequence. Polynucleotides comprising an appropriate coding sequence canbe isolated from human cells or synthesised according to methods wellknown in the art, as described by way of example in Sambrook et al.(1989) Molecular Cloning: A Laboratory Manual, 2^(nd) edition, ColdSpring Harbor Laboratory Press.

[0056] Polynucleotides for use in accordance with the invention mayinclude within them synthetic or modified nucleotides. A number ofdifferent types of modification to polynucleotides are known in the art.These include methylphosphonate and phosphothioate backbones, additionof acridine or polylysine chains at the 3′ and/or 5′ ends of themolecule. Such modifications may be incorporated to enhance the in vivoactivity or life span of the polynucleotide as a therapeutic agent.

[0057] Typically, a polynucleotide for use in accordance with theinvention will include a sequence of nucleotides, which may preferablybe a contiguous sequence of nucleotides, which is capable of hybridisingunder selective conditions to the complement of the coding sequence ofSEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7. Suchhybridisation will occur at a level significantly above background.Background hybridisation may occur, for example, because of other cDNAspresent in a cDNA library. The signal level generated by the interactionbetween a desired coding sequence and the complement of the codingsequence of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7will typically be at least 10 fold, preferably at least 100 fold, asintense as interactions between other polynucleotides and the targetsequence. The intensity of interaction may be measured, for example, byradiolabelling the nucleic acid selected for probing, e.g. with ³²P.Selective hybridisation may typically be achieved using conditions oflow stringency (0.3M sodium chloride and 0.03M sodium citrate at about40° C.), medium stringency (for example, 0.3M sodium chloride and 0.03Msodium citrate at about 50° C.) or high stringency (for example, 0.03Msodium chloride and 0.003M sodium citrate at about 60° C.).

[0058] The coding sequence of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5or SEQ ID NO: 7 may be modified for incorporation into a polynucleotideas defined above by nucleotide substitutions, for example from 1, 2 or 3to 10, 25, 50 or 100 substitutions. Degenerate substitutions may, forexample, be made and/or substitutions may be made which would result ina conservative amino acid substitution when the modified sequence istranslated, for example as shown in the table above. The coding sequenceof SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7 mayalternatively or additionally be modified by one or more insertionsand/or deletions and/or by an extension at either or both ends providedit encodes a polypeptide with the appropriate functional activitycompared to HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein.

[0059] A nucleotide sequence capable of selectively hybridising to thecomplement of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO:7, or at least the coding sequence thereof, will be generally at least70%, preferably at least 80 or 90% and more preferably at least 95% or97%, homologous to such a DNA sequence. This homology may typically beover a region of at least 20, preferably at least 30, for instance atleast 40, 60 or 100 or more contiguous nucleotides of the said DNAsequence.

[0060] Any combination of the above mentioned degrees of homology andminimum size may be used to define nucleic acids comprising desiredcoding sequences, with the more stringent combinations (i.e. higherhomology over longer lengths) being preferred. Thus for example apolynucleotide which is at least 80% homologous over 25. preferably over30 nucleotides may be found suitable, as may be a polynucleotide whichis at least 90% homologous over 40 nucleotides.

[0061] Homologues of polynucleotide or protein sequences as referred toherein may be determined in accordance with well-known means of homologycalculation, e.g. protein homology may be calculated on the basis ofamino acid identity (sometimes referred to as “hard homology”). Forexample the UWGCG Package provides the BESTFIT program which can be usedto calculate homology, for example used on its default settings,(Devereux et al. (1984) Nucleic Acids Research 12, p387-395). The PILEUPand BLAST algorithms can be used to calculate homology or line upsequences or to identify equivalent or corresponding sequences,typically used on their default settings, for example as described inAltschul S. F. (1993) J Mol Evol 36:290-300; Altschul, S, F et al.(1990) J Mol Biol 215:403-10.

[0062] Software for performing BLAST analyses is publicly availablethrough the National Center for Biotechnology Information(http://www.ncbi.nlm.nih.gov/). This algorithm involves firstidentifying high scoring sequence pair (HSPs) by identifying short wordsof length W in the query sequence that either match or satisfy somepositive-valued threshold score T when aligned with a word of the samelength in a database sequence. T is referred to as the neighbourhoodword score threshold (Altschul et al, supra). These initialneighbourhood word hits act as seeds for initiating searches to findHSP=s containing them. The word hits are extended in both directionsalong each sequence for as far as the cumulative alignment score can beincreased. Extensions for the word hits in each direction are haltedwhen: the cumulative alignment score falls off by the quantity X fromits maximum achieved value; the cumulative score goes to zero or below,due to the accumulation of one or more negative-scoring residuealignments; or the end of either sequence is reached. The BLASTalgorithm parameters W, T and X determine the sensitivity and speed ofthe alignment. The BLAST program uses as defaults a word length (W) of11, the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1992) Proc.Natl. Acad. Sci. USA 89: 10915-10919) alignments (B) of 50, expectation(E) of 10, M=5, N=4, and a comparison of both strands.

[0063] The BLAST algorithm performs a statistical analysis of thesimilarity between two sequences; see e.g., Karlin and Altschul (1993)Proc. Natl. Acad. Sci. USA 90: 5873-5787. One measure of similarityprovided by the BLAST algorithm is the smallest sum probability (P(N)),which provides an indication of the probability by which a match betweentwo nucleotide or amino acid sequences would occur by chance. Forexample, a sequence is considered similar to another sequence if thesmallest sum probability in comparison of the first sequence to thesecond sequence is less than about 1, preferably less than about 0.1,more preferably less than about 0.01, and most preferably less thanabout 0.001.

[0064] As indicated above, a polynucleotide for use in accordance withthe invention in substitution for direct administration of HuIFRG-1,HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein or a functional variant thereofmay preferably be in the form of an expression vector. Expressionvectors are routinely constructed in the art of molecular biology andmay, for example, involve the use of plasmid DNA and appropriateinitiators, promoters, enhancers and other elements, such as for examplepolyadenylation signals which may be necessary, and which are positionedin the correct orientation, in order to allow for protein expression.Such vectors may be viral vectors. Examples of suitable viral vectorsinclude herpes simplex viral vectors. replication-defectiveretroviruses, including lentiviruses, adenoviruses, adeno-associatedvirus. HPV viruses (such as HPV-16 and HPV-18) and attenuated influenzavirus vectors. Other suitable vectors would be apparent to personsskilled in the art. By way of further example in this regard referenceis made again to Sambrook et al., 1989 (supra).

[0065] A polynucleotide capable of expressing in vivo an antisensesequence to a coding sequence for the amino acid sequence defined bySEQ. ID. No. 2, or a naturally-occurring variant thereof, for use intherapeutic treatment of a human or non-human animal is also envisagedas constituting an additional aspect of the invention. Again, such apolynucleotide may preferably be in the form of an expression vector.Such a polynucleotide will find use in treatment of diseases associatedwith upregulation of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein.

[0066] It will be appreciated that antibodies to HuIFRG-1, HuIFRG-2,HuIFRG-3 or HuIFRG-4 protein and antigen-binding fragments thereof mayfind similar use.

[0067] Pharmaceutical Compositions

[0068] A polypeptide for use in accordance with the invention istypically formulated for administration with a pharmaceuticallyacceptable carrier or diluent. The pharmaceutical carrier or diluent maybe, for example, an isotonic solution. For example, solid oral forms maycontain, together with the active compound, diluents, e.g. lactose,dextrose, saccharose, cellulose, corn starch or potato starch;lubricants, e.g. silica, talc, stearic acid, magnesium or calciumstearate and or polyethelene glycols; binding agents, e.g. starches,arabic gums, gelatin, methyl cellulose, carboxymethylcellulose orpolyvinyl pyrrolidone; desegregating agents, e.g. starch, alginic acid,alginates or sodium starch glycolate; effervescing mixtures; dyestuffs;sweeteners; wetting agents, such as lecithin, polysorbates,laurylsulphates; and, in general, non-toxic and pharmacologicallyinactive substances used in pharmaceutical formulations. Suchpharmaceutical preparations may be manufactured in known manner, forexample, by means of mixing, granulating, tableting, sugar-coating, orfilm coating processes.

[0069] Liquid dispersions for oral administration may be syrups,emulsions and suspensions. The syrups may contain as carriers, forexample, saccharose or saccharose with glycerine and/or mannitol and/orsorbitol.

[0070] Suspensions and emulsions may contain as carrier, for example anatural gum. agar, sodium alginate, pectin, methyl cellulose,carboxymethylcellulose, or polyvinyl alcohol. The suspensions orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier. e.g. sterilewater, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and ifdesired, a suitable amount of lidocaine hydrochloride.

[0071] Solutions for intravenous injection or infusions may contain ascarrier, for example, sterile water or preferably they may be in theform of sterile, aqueous, isotonic saline solutions.

[0072] The dose of polypeptide for use in accordance with the inventionmay be determined according to various parameters, especially accordingto the substance used: the age, weight and condition of the patient tobe treated; the route of administration; and the required regimen. Aphysician will be able to determine the required route of administrationand dosage for any particular patient. A typical daily dose is fromabout 0.1 to 50 mg per kg, preferably from about 0.1 mg/kg to 10 mg/kgof body weight, according to the activity of the specific activecompound, the age, weight and condition of the subject to be treated,and the frequency and route of administration. Preferably, daily dosagelevels are from 5 mg to 2 g.

[0073] A polynucleotide for use in accordance with the invention willalso typically be formulated for administration with a pharmaceuticallyacceptable carrier or diluent. Such a polynucleotide may be administeredby any known technique whereby expression of the desired polypeptide canbe attained in vivo. For example, the polynucleotide may be deliveredintradermally, subcutaneously, or intramuscularly. Alternatively, thepolynucleotide may be delivered across the skin using aparticle-mediated delivery device. A polynucleotide for use inaccordance with the invention may be administered by intranasal or oraladministration.

[0074] A non-viral vector for use in accordance with the invention maybe packaged into liposomes or into surfactant. Uptake of nucleic acidconstructs for use in accordance with the invention may be enhanced byseveral known transfection techniques, for example those including theuse of transfection agents. Examples of these agents include cationicagents, for example calcium phosphate and DEAE dextran and lipofectants,for example lipophectam and transfectam. The dosage of the nucleic acidto be administered can be varied. Typically, the nucleic acid isadministered in the range of from 1 pg to 1 mg, preferably from 1 pg to10 □g nucleic acid for particle-mediated gene delivery and from 10 □g to1 mg for other routes.

[0075] Prediction of Type 1 Interferon Responsiveness

[0076] As also indicated above, in a still further aspect the presentinvention provides a method of predicting responsiveness of a patient totreatment with a Type 1 interferon, e.g. IFN-α treatment such as IFN-αtreatment by an oromucosal route or intravenously, which comprisesdetermining the level of one or more of HuIFRG-1. HuIFRG-2, HuIFRG-3,HuIFRG-4 protein and naturally-occurring variants thereof, or one ormore corresponding mRNAs, in a cell sample from said patient, whereinsaid sample is taken from said patient following administration of aType 1 interferon or is treated prior to said determining with a Type 1interferon in vitro.

[0077] Preferably, the Type 1 interferon for testing responsiveness willbe the Type 1 interferon selected for treatment. It may be administeredby the proposed treatment route and at the proposed treatment dose.Preferably, the subsequent sample analysed may be, for example, a bloodsample or a sample of peripheral blood mononuclear cells (PBMCs)isolated from a blood sample.

[0078] More conveniently and preferably, a sample obtained from thepatient comprising PBMCs isolated from blood may be treated in vitrowith a Type 1 interferon, e.g. at a dosage range of about 1 to 10,000IU/ml. Such treatment may be for a period of hours, e.g. about 7 to 8hours. Preferred treatment conditions for such in vitro testing may bedetermined by testing PBMCs taken from normal donors with the sameinterferon and looking for upregulation of an appropriate expressionproduct. Again, the Type 1 interferon employed will preferably be theType 1 interferon proposed for treatment of the patient, e.g.recombinant IFN-α. PBMCs for such testing may be isolated inconventional manner from a blood sample using Ficoll-Hypaque densitygradients. An example of a suitable protocol for such in vitro testingof Type 1 interferon responsiveness is provided in Example 6 below.

[0079] The sample, if appropriate after in vitro treatment with a Type 1interferon, may be analysed for the level of HuIFRG-1, HuIFRG-2,HuIFRG-3 or HuIFRG-4 protein or a naturally-occurring variant thereof.This may be done using an antibody or antibodies capable of specificallybinding one or more of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 proteinand naturally-occurring variants thereof, eg. allelic variants thereof.Preferably, however, the sample will be analysed for mRNA encodingHuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein or anaturally-occurring variant thereof. Such mRNA analysis may employ anyof the techniques known for detection of mRNAs, e.g. Northern blotdetection or mRNA differential display. A variety of known nucleic acidamplification protocols may be employed to amplify any mRNA of interestpresent in the sample, or a portion thereof, prior to detection. ThemRNA of interest, or a corresponding amplified nucleic acid, may beprobed for using a nucleic acid probe attached to a solid support. Sucha solid support may be a micro-array carrying probes to determine thelevel of further mRNAs or amplification products thereof correspondingto Type 1 interferon upregulated genes, e.g. such genes identified asupregulated in response to oromucosal or intravenous administration ofIFN-α. Methods for constructing such micro-arrays (also referred tocommonly as nucleic acid, probe or DNA chips) are well-known (see, forexample, EP-B 0476014 and 0619321 of Affymax Technologies N.V. andNature Genetics Supplement January 1999 entitled “The ChippingForecast”).

[0080] The following examples illustrate the invention:

EXAMPLES Example 1

[0081] Previous experiments had shown that the application of 5 μl ofcrystal violet to each nostril of a normal adult mouse using a P20Eppendorf micropipette resulted in an almost immediate distribution ofthe dye over the whole surface of the oropharyngeal cavity. Staining ofthe oropharyngeal cavity was still apparent some 30 minutes afterapplication of the dye. These results were confirmed by using¹²⁵I-labelled recombinant human IFN-□1-8 applied in the same manner. Thesame method of administration was employed to effect oromucosaladministration in the studies which are described below.

[0082] Six week old, male DBA/2 mice were treated with either 100,000 IUof recombinant murine interferon α (IFN α) purchased from LifeTechnologies Inc, in phosphate buffered saline (PBS), 10 μg ofrecombinant human interleukin 15 (IL-15) purchased from ProteinInstitute Inc, PBS containing 100 μg/ml of bovine serum albumin (BSA),or left untreated. Eight hours later, the mice were sacrificed bycervical dislocation and the lymphoid tissue was removed surgically fromthe oropharyngeal cavity and snap frozen in liquid nitrogen and storedat −80° C. RNA was extracted from the lymphoid tissue by the method ofChomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159) andsubjected to mRNA Differential Display Analysis (Lang, P. and Pardee, A.B., Science, 257, 967-971).

[0083] Differential Display Analysis

[0084] Differential display analysis was carried out using the “MessageClean” and “RNA image” kits of the GenHunter Corporation essentially asdescribed by the manufacturer. Briefly, RNA was treated with RNase-freeDNase, and 1 μg was reverse-transcribed in 100 μl of reaction bufferusing either one or the other of the three one-base anchored oligo-(dT)primers A, C, or G. RNA was also reverse-transcribed using one or theother of the 9 two-base anchored oligo-(dT) primers AA, CC, GG, AC, CA,GA, AG, CG, GC. All the samples to be compared were reverse transcribedin the same experiment, separated into aliquots and frozen. Theamplification was performed with only 1 μl of the reverse transcriptionsample in 10 μl of amplification mixture containing Taq DNA polymeraseand α-³³P dATP (3,000 Ci/mmole). Eighty 5′ end (HAP) random sequenceprimers were used in combination with each of the (HT11) A, C, G, AA,CC, GG, AC, CA, GA, AG, CG or GC primers. Samples were then run on 7%denaturing polyacrylamide gels and exposed to authoradiography. Putativedifferentially expressed bands were cut out, reamplified according tothe instructions of the supplier, and further used as probes tohybridise Northern blots of RNA extracted from the oropharyngeal cavityof IFN treated, IL-15 treated, and excipient treated animals.

[0085] Cloning and Sequencing

[0086] Re-amplified bands from the differential display screen werecloned in the Sfr 1 site of the pPCR-Script SK(+) plasmid (Stratagene),and cDNA amplified from the rapid amplification of cDNA ends wereisolated by TA cloning in the pCR3 plasmid (Invitrogen). DNA wassequenced using an automatic di-deoxy sequencer (Perkin Elmer ABI PRISM377).

[0087] Identification of Human cDNA

[0088] Differentially expressed murine 3′ sequences identified from thedifferential display screen were compared with random human expressedsequence tags (EST) present in the dbEST database of GenBank™ of theUnited States National Center for Biotechnology Information (NCBI). Thesequences potentially related to the murine EST isolated from thedifferential display screen were combined in a contig and used toconstruct a human consensus sequence corresponding to a putative cDNA.

[0089] One such cDNA was found to correspond to GenBank cDNA sequenceg4586459. The corresponding polypeptide sequence is GenBank sequenceg4586460, not assigned in GenBank any function.

[0090] Other mouse genes upregulated in lymphoid tissue in response tooromucosal administration of IFN-α as described above have also beenfound to be upregulated in the spleen of mice in response to intravenousadministration of IFN-α. A similar result is anticipated in respect ofthe mouse gene corresponding to the human gene identified by GenbankcDNA accesssion no. g4586459 when intravenous administration of IFN-α iscarried out as described in Example 5 below.

[0091] Furthermore, mRNAs corresponding to human gene analogues of mousegenes found to be upregulated in response to oromucosal and intravenousadministration of IFN-α have been found to be enhanced in humanperipheral blood mononuclear cells following treatment with IFN-α invitro. The same result is anticipated for mRNA corresponding to the cDNAas set forth in SEQ ID NO: 1 when human peripheral blood mononuclearcells are treated with IFN-α as described in Example 6 below.

Example 2

[0092] Previous experiments had shown that the application of 5 μl ofcrystal violet to each nostril of a normal adult mouse using a P20Eppendorf micropipette resulted in an almost immediate distribution ofthe dye over the whole surface of the oropharyngeal cavity. Staining ofthe oropharyngeal cavity was still apparent some 30 minutes afterapplication of the dye. These results were confirmed by using¹²⁵I-labelled recombinant human IFN-□1-8 applied in the same manner. Thesame method of administration was employed to effect oromucosaladministration in the studies which are described below.

[0093] Six week old, male DBA/2 mice were treated with either 100,000 IUof recombinant murine interferon α (IFN α) purchased from LifeTechnologies Inc, in phosphate buffered saline (PBS), 10 μg ofrecombinant human interleukin 15 (IL-15) purchased from ProteinInstitute Inc, PBS containing 100 μg/ml of bovine serum albumin (BSA),or left untreated. Eight hours later, the mice were sacrificed bycervical dislocation and the lymphoid tissue was removed surgically fromthe oropharyngeal cavity and snap frozen in liquid nitrogen and storedat −80° C. RNA was extracted from the lymphoid tissue by the method ofChomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159) andsubjected to mRNA Differential Display Analysis (Lang, P. and Pardee, A.B., Science, 257, 967-971).

[0094] Differential Display Analysis

[0095] Differential display analysis was carried out using the “MessageClean” and “RNA image” kits of the GenHunter Corporation essentially asdescribed by the manufacturer. Briefly, RNA was treated with RNase-freeDNase, and 1 μg was reverse-transcribed in 100 μl of reaction bufferusing either one or the other of the three one-base anchored oligo-(dT)primers A, C, or G. RNA was also reverse-transcribed using one or theother of the 9 two-base anchored oligo-(dT) primers AA, CC, GG, AC, CA,GA, AG, CG, GC. All the samples to be compared were reverse transcribedin the same experiment, separated into aliquots and frozen. Theamplification was performed with only 1 μl of the reverse transcriptionsample in 10 μl of amplification mixture containing Taq DNA polymeraseand α-³³P dATP (3,000 Ci/mmole). Eighty 5′ end (HAP) random sequenceprimers were used in combination with each of the (HT11) A, C, G, AA,CC, GG, AC, CA, GA, AG, CG or GC primers. Samples were then run on 7%denaturing polyacrylamide gels and exposed to authoradiography. Putativedifferentially expressed bands were cut out, reamplified according tothe instructions of the supplier, and further used as probes tohybridise Northern blots of RNA extracted from the oropharyngeal cavityof IFN treated, IL-15 treated, and excipient treated animals.

[0096] Cloning and Sequencing

[0097] Re-amplified bands from the differential display screen werecloned in the Sfr 1 site of the pPCR-Script SK(+) plasmid (Stratagene),and cDNA amplified from the rapid amplification of cDNA ends wereisolated by TA cloning in the pCR3 plasmid (Invitrogen). DNA wassequenced using an automatic di-deoxy sequencer (Perkin Elmer ABI PRISM377).

[0098] Identification of Human cDNA

[0099] Differentially expressed murine 3′ sequences identified from thedifferential display screen were compared with random human expressedsequence tags (EST) present in the dbEST database of GenBank™ of theUnited States National Center for Biotechnology Information (NCBI). Thesequences potentially related to the murine EST isolated from thedifferential display screen were combined in a contig and used toconstruct a human consensus sequence corresponding to a putative cDNA.

[0100] One such cDNA was found to correspond to GenBank cDNA sequenceg2342476. The corresponding polypeptide sequence is GenBank sequenceg2342477, not assigned in GenBank any function.

[0101] Other mouse genes upregulated in lymphoid tissue in response tooromucosal administration of IFN-α as described above have also beenfound to be upregulated in the spleen of mice in response to intravenousadministration of IFN-α. A similar result is anticipated in respect ofthe mouse gene corresponding to the human gene identified by GenbankcDNA accesssion no. g2342476 when intravenous administration of IFN-α iscarried out as described in Example 5 below.

[0102] Furthermore, mRNAs corresponding to human gene analogues of mousegenes found to be upregulated in response to oromucosal and intravenousadministration of IFN-α have been found to be enhanced in humanperipheral blood mononuclear cells following treatment with IFN-α invitro. The same result is anticipated for mRNA corresponding to the cDNAas set forth in SEQ. ID. No. 3 when human peripheral blood mononuclearcells are treated with IFN-α as described in Example 6 below.

Example 3

[0103] Previous experiments had shown that the application of 5 μl ofcrystal violet to each nostril of a normal adult mouse using a P20Eppendorf micropipette resulted in an almost immediate distribution ofthe dye over the whole surface of the oropharyngeal cavity. Staining ofthe oropharyngeal cavity was still apparent some 30 minutes afterapplication of the dye. These results were confirmed by using¹²⁵I-labelled recombinant human IFN-□1-8 applied in the same manner. Thesame method of administration was employed to effect oromucosaladministration in the studies which are described below.

[0104] Six week old, male DBA/2 mice were treated with either 100,000 IUof recombinant murine interferon α (IFN α) purchased from LifeTechnologies Inc, in phosphate buffered saline (PBS), 10 μg ofrecombinant human interleukin 15 (IL-15) purchased from ProteinInstitute Inc, PBS containing 100 μg/ml of bovine serum albumin (BSA),or left untreated. Eight hours later, the mice were sacrificed bycervical dislocation and the lymphoid tissue was removed surgically fromthe oropharyngeal cavity and snap frozen in liquid nitrogen and storedat −80° C. RNA was extracted from the lymphoid tissue by the method ofChomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159) andsubjected to mRNA Differential Display Analysis (Lang, P. and Pardee, A.B., Science, 257, 967-971).

[0105] Differential Display Analysis

[0106] Differential display analysis was carried out using the “MessageClean” and “RNA image” kits of the GenHunter Corporation essentially asdescribed by the manufacturer. Briefly, RNA was treated with RNase-freeDNase, and 1 μg was reverse-transcribed in 100 μl of reaction bufferusing either one or the other of the three one-base anchored oligo-(dT)primers A, C, or G. RNA was also reverse-transcribed using one or theother of the 9 two-base anchored oligo-(dT) primers AA, CC, GG, AC, CA,GA, AG, CG, GC. All the samples to be compared were reverse transcribedin the same experiment, separated into aliquots and frozen. Theamplification was performed with only 1 μl of the reverse transcriptionsample in 10 μl of amplification mixture containing Taq DNA polymeraseand α-³³P dATP (3,000 Ci/mmole). Eighty 5′ end (HAP) random sequenceprimers were used in combination with each of the (HT11) A, C, G, AA,CC, GG, AC, CA, GA, AG, CG or GC primers. Samples were then run on 7%denaturing polyacrylamide gels and exposed to authoradiography. Putativedifferentially expressed bands were cut out. reamplified according tothe instructions of the supplier, and further used as probes tohybridise Northern blots of RNA extracted from the oropharynpeal cavityof IFN treated. IL-15 treated, and excipient treated animals.

[0107] Cloning and Sequencing

[0108] Re-amplified bands from the differential display screen werecloned in the Sfr 1 site of the pPCR-Script SK(+) plasmid (Stratagene),and cDNA amplified from the rapid amplification of cDNA ends wereisolated by TA cloning in the pCR3 plasmid (Invitrogen). DNA wassequenced using an automatic di-deoxy sequencer (Perkin Elmer ABI PRISM377).

[0109] Identification of Human cDNA

[0110] Differentially expressed murine 3′ sequences identified from thedifferential display screen were compared with random human expressedsequence tags (EST) present in the dbEST database of GenBank™ of theUnited States National Center for Biotechnology Information (NCBI). Thesequences potentially related to the murine EST isolated from thedifferential display screen were combined in a contig and used toconstruct a human consensus sequence corresponding to a putative cDNA.

[0111] One such cDNA was found to correspond to GenBank cDNA sequenceg3327161. The corresponding polypeptide sequence is GenBank sequenceg3327162, not assigned in GenBank any function.

[0112] Other mouse genes upregulated in lymphoid tissue in response tooromucosal administration of IFN-α as described above have also beenfound to be upregulated in the spleen of mice in response to intravenousadministration of IFN-α. A similar result is anticipated in respect ofthe mouse gene corresponding to the human gene identified by GenbankcDNA accesssion no. g3327161 when intravenous administration of IFN-α iscarried out as described in Example 5 below.

[0113] Furthermore, mRNAs corresponding to human gene analogues of mousegenes found to be upregulated in response to oromucosal and intravenousadministration of IFN-α have been found to be enhanced in humanperipheral blood mononuclear cells following treatment with IFN-α invitro. The same result is anticipated for mRNA corresponding to the cDNAas set forth in SEQ. ID. No. 5 when human peripheral blood mononuclearcells are treated with IFN-α as described in Example 6 below.

Example 4

[0114] Previous experiments had shown that the application of 5 μl ofcrystal violet to each nostril of a normal adult mouse using a P20Eppendorf micropipette resulted in an almost immediate distribution ofthe dye over the whole surface of the oropharyngeal cavity. Staining ofthe oropharyngeal cavity was still apparent some 30 minutes afterapplication of the dye. These results were confirmed by using¹²⁵I-labelled recombinant human IFN-□1-8 applied in the same manner. Thesame method of administration was employed to effect oromucosaladministration in the studies which are described below.

[0115] Six week old, male DBA/2 mice were treated with either 100,000 IUof recombinant murine interferon a (IFN α) purchased from LifeTechnologies Inc, in phosphate buffered saline (PBS), 10 μg ofrecombinant human interleukin 15 (IL-15) purchased from ProteinInstitute Inc, PBS containing 100 μg/ml of bovine serum albumin (BSA),or left untreated. Eight hours later, the mice were sacrificed bycervical dislocation and the lymphoid tissue was removed surgically fromthe oropharyngeal cavity and snap frozen in liquid nitrogen and storedat −80° C. RNA was extracted from the lymphoid tissue by the method ofChomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159) andsubjected to mRNA Differential Display Analysis (Lang, P. and Pardee, A.B., Science, 257, 967-971).

[0116] Differential Display Analysis

[0117] Differential display analysis was carried out using the “MessageClean” and “RNA image” kits of the GenHunter Corporation essentially asdescribed by the manufacturer. Briefly, RNA was treated with RNase-freeDNase, and 1 μg was reverse-transcribed in 100 μl of reaction bufferusing either one or the other of the three one-base anchored oligo-(dT)primers A, C, or G. RNA was also reverse-transcribed using one or theother of the 9 two-base anchored oligo-(dT) primers AA, CC, GG, AC, CA,GA, AG, CG, GC. All the samples to be compared were reverse transcribedin the same experiment, separated into aliquots and frozen. Theamplification was performed with only 1 μl of the reverse transcriptionsample in 10 μl of amplification mixture containing Taq DNA polymeraseand α-³³P dATP (3,000 Ci/mmole). Eighty 5′ end (HAP) random sequenceprimers were used in combination with each of the (HT11) A, C, G, AA,CC, GG, AC, CA, GA, AG, CG or GC primers. Samples were then run on 7%denaturing polyacrylamide gels and exposed to authoradiography. Putativedifferentially expressed bands were cut out, reamplified according tothe instructions of the supplier, and further used as probes tohybridise Northern blots of RNA extracted from the oropharyngeal cavityof IFN treated, IL-15 treated, and excipient treated animals.

[0118] Cloning and Sequencing

[0119] Re-amplified bands from the differential display screen werecloned in the Sfr 1 site of the pPCR-Script SK(+) plasmid (Stratagene),and cDNA amplified from the rapid amplification of cDNA ends wereisolated by TA cloning in the pCR3 plasmid (Invitrogen). DNA wassequenced using an automatic di-deoxy sequencer (Perkin Elmer ABI PRISM377).

[0120] Identification of Human cDNA

[0121] Differentially expressed murine 3′ sequences identified from thedifferential display screen were compared with random human expressedsequence tags (EST) present in the dbEST database of GenBank™ of theUnited States National Center for Biotechnology Information (NCBI). Thesequences potentially related to the murine EST isolated from thedifferential display screen were combined in a contig and used toconstruct a human consensus sequence corresponding to a putative cDNA.

[0122] One such cDNA was found to correspond to GenBank cDNA sequenceg4529886. The corresponding polypeptide sequence is GenBank sequenceg4529888, not assigned in GenBank any function.

[0123] Other mouse genes upregulated in lymphoid tissue in response tooromucosal administration of IFN-α as described above have also beenfound to be upregulated in the spleen of mice in response to intravenousadministration of IFN-α. A similar result is anticipated in respect ofthe mouse gene corresponding to the human gene identified by GenbankcDNA accesssion no. g4529886 when intravenous administration of IFN-α iscarried out as described in Example 5 below.

[0124] Furthermore, mRNAs corresponding to human gene analogues of mousegenes found to be upregulated in response to oromucosal and intravenousadministration of IFN-α have been found to be enhanced in humanperipheral blood mononuclear cells following treatment with IFN-α invitro. The same result is anticipated for mRNA corresponding to the cDNAas set forth in SEQ. ID. No. 7 when human peripheral blood mononuclearcells are treated with IFN-c as described in Example 6 below.

Example 5

[0125] Intravenous Administration of IFN-α

[0126] Male DBA/2 mice are injected intravenously with 100,000 IU ofrecombinant murine IFN-α purchased from Life Technologies Inc. in 200 μlof PBS or treated with an equal volume of PBS alone. Eight hours laterthe animals are sacrificed by cervical dislocation and the spleen wasremoved using conventional procedures. Total RNA was extracted by themethod of Chomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159)and 10.0 μg of total RNA per sample is subjected to Northern blotting inthe presence of glyoxal and hybridised with a cDNA probe for the mRNA ofinterest as described by Dandoy-Dron et al. (J. Biol. Chem. (1998) 273,7691-7697). The blots are first exposed to autoradiography and thenquantified using a Phospholmager according to the manufacturer'sinstructions.

Example 6

[0127] Testing Type 1 Interferon Responsiveness in vitro

[0128] Human peripheral blood mononuclear cells (PBMC) from normaldonors are isolated on Ficoll-Hypaque density gradients and treated invitro with 10,000 IU of recombinant human IFN-α2 (intron A fromSchering-Plough) in PBS or with an equal volume of PBS alone. Eighthours later the cells are centrifuged (800×g for 10 minutes) and thecell pellet recovered. Total RNA is extracted from the cell pellet bythe method of Chomczynski and Sacchi and 10.0 μg of total RNA per sampleis subjected to Northern blotting as described in Example 5 above.

[0129] The same procedure can be used to predict Type 1 interferonresponsiveness using PBMC taken from a patient proposed to be treatedwith a Type 1 interferon.

1 8 1 1640 DNA Homo sapiens CDS (1)..(1407) 1 aat gcc acc tgc ttg aaggct ata tgt gac aag tca cta gag gtt cac 48 Asn Ala Thr Cys Leu Lys AlaIle Cys Asp Lys Ser Leu Glu Val His 1 5 10 15 ctg cag gtt gac gcc atgtac aca aat gtc aaa gta act aat att tgc 96 Leu Gln Val Asp Ala Met TyrThr Asn Val Lys Val Thr Asn Ile Cys 20 25 30 tct gat ggg aca ctc tac tgccag gtg cct tgt aag ggt ctg aac aag 144 Ser Asp Gly Thr Leu Tyr Cys GlnVal Pro Cys Lys Gly Leu Asn Lys 35 40 45 ctc agt gac ctt cta cgt aag atagag gac tac ttc cat tgc aag cac 192 Leu Ser Asp Leu Leu Arg Lys Ile GluAsp Tyr Phe His Cys Lys His 50 55 60 atg acc tct gag tgc ttt gtt tca ttaccc ttc tgt ggg aaa atc tgc 240 Met Thr Ser Glu Cys Phe Val Ser Leu ProPhe Cys Gly Lys Ile Cys 65 70 75 80 ctc ttc cat tgc aaa gga aaa tgg ttacga gta gag atc aca aat gtt 288 Leu Phe His Cys Lys Gly Lys Trp Leu ArgVal Glu Ile Thr Asn Val 85 90 95 cac agc agc cgg gct ctt gat gtt cag ttcctg gac tct ggc act gtg 336 His Ser Ser Arg Ala Leu Asp Val Gln Phe LeuAsp Ser Gly Thr Val 100 105 110 aca tct gta aaa gtg tca gag ctc agg gaaatt cca cct cgg ttt cta 384 Thr Ser Val Lys Val Ser Glu Leu Arg Glu IlePro Pro Arg Phe Leu 115 120 125 caa gaa atg att gca ata cca cct cag gccatt aag tgc tgt tta gca 432 Gln Glu Met Ile Ala Ile Pro Pro Gln Ala IleLys Cys Cys Leu Ala 130 135 140 gat ctt cca caa tct att ggc atg tgg acacca gat gca gtg ctg tgg 480 Asp Leu Pro Gln Ser Ile Gly Met Trp Thr ProAsp Ala Val Leu Trp 145 150 155 160 tta aga gat tct gtt ttg aat tgc tcggac tgt agc att aag gtt aca 528 Leu Arg Asp Ser Val Leu Asn Cys Ser AspCys Ser Ile Lys Val Thr 165 170 175 aaa gtg gat gaa acc aga ggg atc gcacat gtt tat tta ttt acc cct 576 Lys Val Asp Glu Thr Arg Gly Ile Ala HisVal Tyr Leu Phe Thr Pro 180 185 190 aag aac ttc cct gac cct cat cgc agtatt aat cgc cag att aca aat 624 Lys Asn Phe Pro Asp Pro His Arg Ser IleAsn Arg Gln Ile Thr Asn 195 200 205 gca gac ttg tgg aag cat cag aag gatgtg ttt ttg agt gcc ata tcc 672 Ala Asp Leu Trp Lys His Gln Lys Asp ValPhe Leu Ser Ala Ile Ser 210 215 220 agt gga gct gac tct ccc aac agc aaaaat ggc aac atg ccc atg tcg 720 Ser Gly Ala Asp Ser Pro Asn Ser Lys AsnGly Asn Met Pro Met Ser 225 230 235 240 ggc aac act gga gag aat ttc agaaag aac ctc aca gat gtc atc aaa 768 Gly Asn Thr Gly Glu Asn Phe Arg LysAsn Leu Thr Asp Val Ile Lys 245 250 255 aag tcc atg gtg gac cat acg agcgct ttc tcc aca gag gaa ctg cca 816 Lys Ser Met Val Asp His Thr Ser AlaPhe Ser Thr Glu Glu Leu Pro 260 265 270 cct cct gtc cac tta tca aag ccaggg gaa cac atg gat gtg tat gtg 864 Pro Pro Val His Leu Ser Lys Pro GlyGlu His Met Asp Val Tyr Val 275 280 285 cct gtg gcc tgt cac cca ggc tacttc gtc atc cag cct tgg cag gag 912 Pro Val Ala Cys His Pro Gly Tyr PheVal Ile Gln Pro Trp Gln Glu 290 295 300 ata cat aag ttg gaa gtt ctg atggaa gag atg att cta tat tac agc 960 Ile His Lys Leu Glu Val Leu Met GluGlu Met Ile Leu Tyr Tyr Ser 305 310 315 320 gtg tct gaa gag cgc cac atagca gtg gag aaa gac caa gtg tat gct 1008 Val Ser Glu Glu Arg His Ile AlaVal Glu Lys Asp Gln Val Tyr Ala 325 330 335 gca aaa gtg gaa aat aag tggcac agg gtg ctt tta aaa gga atc ctg 1056 Ala Lys Val Glu Asn Lys Trp HisArg Val Leu Leu Lys Gly Ile Leu 340 345 350 acc aat gga ctg gta tct gtgtat gag ctg gat tat ggc aaa cac gaa 1104 Thr Asn Gly Leu Val Ser Val TyrGlu Leu Asp Tyr Gly Lys His Glu 355 360 365 tta gtc aac ata aga aaa gtacag ccc cta gtg gac atg ttc cga aag 1152 Leu Val Asn Ile Arg Lys Val GlnPro Leu Val Asp Met Phe Arg Lys 370 375 380 ctg ccc ttc caa gca gtc acagct caa ctt gca gga gtg aag tgc aac 1200 Leu Pro Phe Gln Ala Val Thr AlaGln Leu Ala Gly Val Lys Cys Asn 385 390 395 400 cag tgg tct gag gag gcttct atg gtg ttt cga aat cat gtg gag aag 1248 Gln Trp Ser Glu Glu Ala SerMet Val Phe Arg Asn His Val Glu Lys 405 410 415 aaa cct ctg gtg gca ctggtg cag aca gtc att gaa aat gct aac cct 1296 Lys Pro Leu Val Ala Leu ValGln Thr Val Ile Glu Asn Ala Asn Pro 420 425 430 tgg gac cgg aaa gta gtggtc tac tta gtg gac aca tcg ttg cca gac 1344 Trp Asp Arg Lys Val Val ValTyr Leu Val Asp Thr Ser Leu Pro Asp 435 440 445 acc gat acc tgg att catgat ttt atg tca gag tat ctg ata gag ctt 1392 Thr Asp Thr Trp Ile His AspPhe Met Ser Glu Tyr Leu Ile Glu Leu 450 455 460 tca aaa gtt aat taatgactgcctc tgaaaccttg acaactaatt cagatttttt 1447 Ser Lys Val Asn 465agcaataaca aaatgtagta ggcttaaaaa aaatcttaac tctgctacat ggctctgact 1507gctgtggggg attgaaaaga atatgcttat gtttgatgaa agatatttaa caagttttgt 1567tttaacagag ttgacttttc aaagaaaatt gtacttgaat tattactata atattagaat 1627aaaaatgttt atc 1640 2 468 PRT Homo sapiens 2 Asn Ala Thr Cys Leu Lys AlaIle Cys Asp Lys Ser Leu Glu Val His 1 5 10 15 Leu Gln Val Asp Ala MetTyr Thr Asn Val Lys Val Thr Asn Ile Cys 20 25 30 Ser Asp Gly Thr Leu TyrCys Gln Val Pro Cys Lys Gly Leu Asn Lys 35 40 45 Leu Ser Asp Leu Leu ArgLys Ile Glu Asp Tyr Phe His Cys Lys His 50 55 60 Met Thr Ser Glu Cys PheVal Ser Leu Pro Phe Cys Gly Lys Ile Cys 65 70 75 80 Leu Phe His Cys LysGly Lys Trp Leu Arg Val Glu Ile Thr Asn Val 85 90 95 His Ser Ser Arg AlaLeu Asp Val Gln Phe Leu Asp Ser Gly Thr Val 100 105 110 Thr Ser Val LysVal Ser Glu Leu Arg Glu Ile Pro Pro Arg Phe Leu 115 120 125 Gln Glu MetIle Ala Ile Pro Pro Gln Ala Ile Lys Cys Cys Leu Ala 130 135 140 Asp LeuPro Gln Ser Ile Gly Met Trp Thr Pro Asp Ala Val Leu Trp 145 150 155 160Leu Arg Asp Ser Val Leu Asn Cys Ser Asp Cys Ser Ile Lys Val Thr 165 170175 Lys Val Asp Glu Thr Arg Gly Ile Ala His Val Tyr Leu Phe Thr Pro 180185 190 Lys Asn Phe Pro Asp Pro His Arg Ser Ile Asn Arg Gln Ile Thr Asn195 200 205 Ala Asp Leu Trp Lys His Gln Lys Asp Val Phe Leu Ser Ala IleSer 210 215 220 Ser Gly Ala Asp Ser Pro Asn Ser Lys Asn Gly Asn Met ProMet Ser 225 230 235 240 Gly Asn Thr Gly Glu Asn Phe Arg Lys Asn Leu ThrAsp Val Ile Lys 245 250 255 Lys Ser Met Val Asp His Thr Ser Ala Phe SerThr Glu Glu Leu Pro 260 265 270 Pro Pro Val His Leu Ser Lys Pro Gly GluHis Met Asp Val Tyr Val 275 280 285 Pro Val Ala Cys His Pro Gly Tyr PheVal Ile Gln Pro Trp Gln Glu 290 295 300 Ile His Lys Leu Glu Val Leu MetGlu Glu Met Ile Leu Tyr Tyr Ser 305 310 315 320 Val Ser Glu Glu Arg HisIle Ala Val Glu Lys Asp Gln Val Tyr Ala 325 330 335 Ala Lys Val Glu AsnLys Trp His Arg Val Leu Leu Lys Gly Ile Leu 340 345 350 Thr Asn Gly LeuVal Ser Val Tyr Glu Leu Asp Tyr Gly Lys His Glu 355 360 365 Leu Val AsnIle Arg Lys Val Gln Pro Leu Val Asp Met Phe Arg Lys 370 375 380 Leu ProPhe Gln Ala Val Thr Ala Gln Leu Ala Gly Val Lys Cys Asn 385 390 395 400Gln Trp Ser Glu Glu Ala Ser Met Val Phe Arg Asn His Val Glu Lys 405 410415 Lys Pro Leu Val Ala Leu Val Gln Thr Val Ile Glu Asn Ala Asn Pro 420425 430 Trp Asp Arg Lys Val Val Val Tyr Leu Val Asp Thr Ser Leu Pro Asp435 440 445 Thr Asp Thr Trp Ile His Asp Phe Met Ser Glu Tyr Leu Ile GluLeu 450 455 460 Ser Lys Val Asn 465 3 1432 DNA Homo sapiens CDS(130)..(810) 3 ttgcagccgc cggcagctac tgcaaggcaa aagccggagt ggacgtgtcttttgaaactg 60 ctgctctttc acttctcagg cgtcaccgag agctcagcac ccaggctgaactctgtacca 120 tttggaaga atg gaa gct gat gca tct gtt gac atg ttt tcc aaagtc ctg 171 Met Glu Ala Asp Ala Ser Val Asp Met Phe Ser Lys Val Leu 1 510 gag cat cag ctg ctt cag act acc aaa ctg gtg gaa gaa cat ttg gat 219Glu His Gln Leu Leu Gln Thr Thr Lys Leu Val Glu Glu His Leu Asp 15 20 2530 tct gaa att caa aaa ctg gat cag atg gat gag gat gaa ttg gaa cgc 267Ser Glu Ile Gln Lys Leu Asp Gln Met Asp Glu Asp Glu Leu Glu Arg 35 40 45ctt aaa gaa aag aga ctc cag gca cta agg aaa gct caa cag cag aaa 315 LeuLys Glu Lys Arg Leu Gln Ala Leu Arg Lys Ala Gln Gln Gln Lys 50 55 60 caagaa tgg ctt tct aaa gga cat ggg gaa tac aga gaa atc cct agt 363 Gln GluTrp Leu Ser Lys Gly His Gly Glu Tyr Arg Glu Ile Pro Ser 65 70 75 gaa agagac ttt ttt caa gaa gtc aag gag agt gaa aat gtg gtt tgc 411 Glu Arg AspPhe Phe Gln Glu Val Lys Glu Ser Glu Asn Val Val Cys 80 85 90 cat ttc tacaga gac tcc aca ttc agg tgt aaa ata cta gac aga cat 459 His Phe Tyr ArgAsp Ser Thr Phe Arg Cys Lys Ile Leu Asp Arg His 95 100 105 110 ctg gcaata ttg tcc aag aaa cac ctc gag acc aat ttt ttg aag ctg 507 Leu Ala IleLeu Ser Lys Lys His Leu Glu Thr Asn Phe Leu Lys Leu 115 120 125 aat gtggaa aaa gca cct ttc ctt tgt gag aga ctg cat atc aaa gtc 555 Asn Val GluLys Ala Pro Phe Leu Cys Glu Arg Leu His Ile Lys Val 130 135 140 att cccaca cta gca ctg cta aaa gat ggg aaa aca caa gat tat gtt 603 Ile Pro ThrLeu Ala Leu Leu Lys Asp Gly Lys Thr Gln Asp Tyr Val 145 150 155 gtt gggttt act gac cta gga aat aca gat gac ttc acc aca gaa act 651 Val Gly PheThr Asp Leu Gly Asn Thr Asp Asp Phe Thr Thr Glu Thr 160 165 170 tta gaatgg agg ctc ggt tct tct gac att ctt aat tac agt gga aat 699 Leu Glu TrpArg Leu Gly Ser Ser Asp Ile Leu Asn Tyr Ser Gly Asn 175 180 185 190 ttaatg gag cca cca ttt cag aac caa aag aaa ttt gga aca aac ttc 747 Leu MetGlu Pro Pro Phe Gln Asn Gln Lys Lys Phe Gly Thr Asn Phe 195 200 205 acaaag ctg gaa aag aaa act atg cga gga aag aaa tat gat tca gac 795 Thr LysLeu Glu Lys Lys Thr Met Arg Gly Lys Lys Tyr Asp Ser Asp 210 215 220 tctgat gat gat tag agctcaataa ttctttgtaa attgtctttt tttttctgct 850 Ser AspAsp Asp tcagatttaa atgtgttttt aaaattctat taatgtctat acattggtcacctaaatact 910 catattctcg agttttatac agttgtatca catcgaaaag tgtctttactgttttctgtg 970 tggccatcat gtttaagttg aggaaactca gttcttaaat tatctgggaagggtctggat 1030 tctctatttt tgagattgac tttatcacaa tatgattctt acatctttataccatttaca 1090 attgtgtttt agatctacag agttagaaat tcgraaacta ttccaggactaattcttaat 1150 cggcattatt tatacaagag gtcaagtaac atttactagc gcaatactgcacttgtaaat 1210 gaattataaa cgctcttctg gaatatattt aaataaccat taaagaactgcttattcatt 1270 ctggacactg catgttgatg ttgaatcaac tgatgccagc agaaagctattttgatttgt 1330 gaacatactg ccttatttaa agggtcctga ttgcttgtat tttaagacattcattaaaaa 1390 gaaaccagga aacacttttg aaataacagc ataaggaact tc 1432 4226 PRT Homo sapiens 4 Met Glu Ala Asp Ala Ser Val Asp Met Phe Ser LysVal Leu Glu His 1 5 10 15 Gln Leu Leu Gln Thr Thr Lys Leu Val Glu GluHis Leu Asp Ser Glu 20 25 30 Ile Gln Lys Leu Asp Gln Met Asp Glu Asp GluLeu Glu Arg Leu Lys 35 40 45 Glu Lys Arg Leu Gln Ala Leu Arg Lys Ala GlnGln Gln Lys Gln Glu 50 55 60 Trp Leu Ser Lys Gly His Gly Glu Tyr Arg GluIle Pro Ser Glu Arg 65 70 75 80 Asp Phe Phe Gln Glu Val Lys Glu Ser GluAsn Val Val Cys His Phe 85 90 95 Tyr Arg Asp Ser Thr Phe Arg Cys Lys IleLeu Asp Arg His Leu Ala 100 105 110 Ile Leu Ser Lys Lys His Leu Glu ThrAsn Phe Leu Lys Leu Asn Val 115 120 125 Glu Lys Ala Pro Phe Leu Cys GluArg Leu His Ile Lys Val Ile Pro 130 135 140 Thr Leu Ala Leu Leu Lys AspGly Lys Thr Gln Asp Tyr Val Val Gly 145 150 155 160 Phe Thr Asp Leu GlyAsn Thr Asp Asp Phe Thr Thr Glu Thr Leu Glu 165 170 175 Trp Arg Leu GlySer Ser Asp Ile Leu Asn Tyr Ser Gly Asn Leu Met 180 185 190 Glu Pro ProPhe Gln Asn Gln Lys Lys Phe Gly Thr Asn Phe Thr Lys 195 200 205 Leu GluLys Lys Thr Met Arg Gly Lys Lys Tyr Asp Ser Asp Ser Asp 210 215 220 AspAsp 225 5 4263 DNA Homo sapiens CDS (1)..(3705) 5 ggg aat acc cag cttcct ccc cgc aac ccg gtg aaa gcc aac gca atg 48 Gly Asn Thr Gln Leu ProPro Arg Asn Pro Val Lys Ala Asn Ala Met 1 5 10 15 ttc ggt gcg ggg gacgag gac gac acc gat ttc ctc tcg ccg agc ggc 96 Phe Gly Ala Gly Asp GluAsp Asp Thr Asp Phe Leu Ser Pro Ser Gly 20 25 30 ggt gcc aga ttg gcc tcactt ttt gga ctg gat cag gca gct gct ggc 144 Gly Ala Arg Leu Ala Ser LeuPhe Gly Leu Asp Gln Ala Ala Ala Gly 35 40 45 cat gga aat gaa ttt ttc cagtac aca gcc cca aaa cag cct aag aaa 192 His Gly Asn Glu Phe Phe Gln TyrThr Ala Pro Lys Gln Pro Lys Lys 50 55 60 ggc cag gga acg gca gca aca ggaaat cag gca aca cca aaa aca gca 240 Gly Gln Gly Thr Ala Ala Thr Gly AsnGln Ala Thr Pro Lys Thr Ala 65 70 75 80 cca gcc acc atg agc act ccc acaata ctg gtc gca aca gca gtc cat 288 Pro Ala Thr Met Ser Thr Pro Thr IleLeu Val Ala Thr Ala Val His 85 90 95 gca tat cga tac aca aat ggt caa tatgta aag cag ggc aaa ttt ggt 336 Ala Tyr Arg Tyr Thr Asn Gly Gln Tyr ValLys Gln Gly Lys Phe Gly 100 105 110 gct gca gtt ctg ggg aac cac aca gccaga gag tat agg att ctt ctt 384 Ala Ala Val Leu Gly Asn His Thr Ala ArgGlu Tyr Arg Ile Leu Leu 115 120 125 tat atc agt caa caa cag cca gtt acggtt gct agg att cat gtg aac 432 Tyr Ile Ser Gln Gln Gln Pro Val Thr ValAla Arg Ile His Val Asn 130 135 140 ttt gag cta atg gtt cgg ccc aat aactat agc acc ttt tat gat gac 480 Phe Glu Leu Met Val Arg Pro Asn Asn TyrSer Thr Phe Tyr Asp Asp 145 150 155 160 cag aga cag aac tgg tcc atc atgttt gag tcg gaa aag gct gct gtg 528 Gln Arg Gln Asn Trp Ser Ile Met PheGlu Ser Glu Lys Ala Ala Val 165 170 175 gag ttc aat aag cag gtg tgc attgct aag tgc aac agt acc tct tcc 576 Glu Phe Asn Lys Gln Val Cys Ile AlaLys Cys Asn Ser Thr Ser Ser 180 185 190 ctg gat gca gtg ctc tcc cag gacctc att gtg gca gac ggc cct gct 624 Leu Asp Ala Val Leu Ser Gln Asp LeuIle Val Ala Asp Gly Pro Ala 195 200 205 gta gaa gtt gga gat tct ttg gaagtg gcc tat acc ggc tgg ctc ttt 672 Val Glu Val Gly Asp Ser Leu Glu ValAla Tyr Thr Gly Trp Leu Phe 210 215 220 cag aat cat gtg ctg ggc cag gttttc gac tcc act gct aac aaa gat 720 Gln Asn His Val Leu Gly Gln Val PheAsp Ser Thr Ala Asn Lys Asp 225 230 235 240 aag ttg ctt cgc ttg aag ttagga tca gga aaa gtc atc aag ggc tgg 768 Lys Leu Leu Arg Leu Lys Leu GlySer Gly Lys Val Ile Lys Gly Trp 245 250 255 gag gat gga atg ctg ggc atgaaa aaa gga gga aag cga ttg ctt att 816 Glu Asp Gly Met Leu Gly Met LysLys Gly Gly Lys Arg Leu Leu Ile 260 265 270 gtc cct cca gcc tgt gct gttggc tca gaa ggg gta ata ggc tgg act 864 Val Pro Pro Ala Cys Ala Val GlySer Glu Gly Val Ile Gly Trp Thr 275 280 285 caa gca acg gac tcg atc ctggtg ttc gag gtg gag gtt agg cgg gtg 912 Gln Ala Thr Asp Ser Ile Leu ValPhe Glu Val Glu Val Arg Arg Val 290 295 300 aag ttt gcc aga gat tct ggctct gat ggt cac agt gtt agt tcc cgc 960 Lys Phe Ala Arg Asp Ser Gly SerAsp Gly His Ser Val Ser Ser Arg 305 310 315 320 gat tct gca gct ccg tctccc atc cct ggt gct gac aac ctc tct gct 1008 Asp Ser Ala Ala Pro Ser ProIle Pro Gly Ala Asp Asn Leu Ser Ala 325 330 335 gat cct gtt gtg tca ccaccc aca tca ata cct ttc aaa tca ggg gag 1056 Asp Pro Val Val Ser Pro ProThr Ser Ile Pro Phe Lys Ser Gly Glu 340 345 350 cca gct ctt cgt acc aaatct aac tcc ctc agt gaa caa ctt gca ata 1104 Pro Ala Leu Arg Thr Lys SerAsn Ser Leu Ser Glu Gln Leu Ala Ile 355 360 365 aat aca agt ccc gat gcagtc aaa gcc aag ttg atc tct cgg atg gct 1152 Asn Thr Ser Pro Asp Ala ValLys Ala Lys Leu Ile Ser Arg Met Ala 370 375 380 aaa atg ggc cag ccc atgctg ccc atc ctt cca cca cag ctg gat tcc 1200 Lys Met Gly Gln Pro Met LeuPro Ile Leu Pro Pro Gln Leu Asp Ser 385 390 395 400 aat gat tca gaa atcgaa gat gtg aac act ctg caa gga ggt ggg cag 1248 Asn Asp Ser Glu Ile GluAsp Val Asn Thr Leu Gln Gly Gly Gly Gln 405 410 415 cct gtg gtg act ccgtcc gtc cag ccc tct ctt cag ccg gcc cat cca 1296 Pro Val Val Thr Pro SerVal Gln Pro Ser Leu Gln Pro Ala His Pro 420 425 430 gcg tta cca cag atgacc tca cag gca cct cag cca tct gtt act ggg 1344 Ala Leu Pro Gln Met ThrSer Gln Ala Pro Gln Pro Ser Val Thr Gly 435 440 445 ctc cag gca cct tctgct gcc tta atg caa gtg tca tct ctc gat tcc 1392 Leu Gln Ala Pro Ser AlaAla Leu Met Gln Val Ser Ser Leu Asp Ser 450 455 460 cac tca gct gta tctgga aat gcc caa tcc ttt cag ccc tat gca ggt 1440 His Ser Ala Val Ser GlyAsn Ala Gln Ser Phe Gln Pro Tyr Ala Gly 465 470 475 480 atg caa gcc tacgct tat ccc cag gca tct gcc gtc acc tcc cag ctg 1488 Met Gln Ala Tyr AlaTyr Pro Gln Ala Ser Ala Val Thr Ser Gln Leu 485 490 495 cag ccc gtt cggcct ttg tac cca gca ccg ctc tct cag cct ccc cat 1536 Gln Pro Val Arg ProLeu Tyr Pro Ala Pro Leu Ser Gln Pro Pro His 500 505 510 ttc caa gga tcaggt gat atg gct tca ttt ctc atg act gaa gcc cgg 1584 Phe Gln Gly Ser GlyAsp Met Ala Ser Phe Leu Met Thr Glu Ala Arg 515 520 525 caa cat aac actgaa att cga atg gca gtc agc aaa gtg gct gat aaa 1632 Gln His Asn Thr GluIle Arg Met Ala Val Ser Lys Val Ala Asp Lys 530 535 540 atg gat cat ctcatg act aag gtt gaa gag tta cag aaa cat agt gct 1680 Met Asp His Leu MetThr Lys Val Glu Glu Leu Gln Lys His Ser Ala 545 550 555 560 ggc aat tccatg ctt att cct agc atg tca gtt aca atg gaa aca agc 1728 Gly Asn Ser MetLeu Ile Pro Ser Met Ser Val Thr Met Glu Thr Ser 565 570 575 atg att atgagc aac atc cag cga atc att cag gaa aat gaa aga ttg 1776 Met Ile Met SerAsn Ile Gln Arg Ile Ile Gln Glu Asn Glu Arg Leu 580 585 590 aag caa gagatc ctt gaa aag agc aat cgg ata gaa gaa cag aat gac 1824 Lys Gln Glu IleLeu Glu Lys Ser Asn Arg Ile Glu Glu Gln Asn Asp 595 600 605 aag att agtgaa cta att gaa cga aat cag agg tat gtt gag cag agt 1872 Lys Ile Ser GluLeu Ile Glu Arg Asn Gln Arg Tyr Val Glu Gln Ser 610 615 620 aac ctg atgatg gag aag agg aac aac tca ctt cag aca gcc aca gaa 1920 Asn Leu Met MetGlu Lys Arg Asn Asn Ser Leu Gln Thr Ala Thr Glu 625 630 635 640 aac acacag gca aga gta ttg cat gct gaa caa gag aag gcc aag gtg 1968 Asn Thr GlnAla Arg Val Leu His Ala Glu Gln Glu Lys Ala Lys Val 645 650 655 aca gaggag tta gca gcg gcc act gcg cag gtc tct cat ctg cag ctg 2016 Thr Glu GluLeu Ala Ala Ala Thr Ala Gln Val Ser His Leu Gln Leu 660 665 670 aaa atgact gct cac caa aaa aag gaa aca gag ctg cag atg cag ctg 2064 Lys Met ThrAla His Gln Lys Lys Glu Thr Glu Leu Gln Met Gln Leu 675 680 685 aca gaaagc ctg aag gag aca gat ctt ctc agg ggc cag ctc acc aaa 2112 Thr Glu SerLeu Lys Glu Thr Asp Leu Leu Arg Gly Gln Leu Thr Lys 690 695 700 gtg caggca aag ctc tca gag ctc caa gaa acc tct gag caa gca cag 2160 Val Gln AlaLys Leu Ser Glu Leu Gln Glu Thr Ser Glu Gln Ala Gln 705 710 715 720 tccaaa ttc aaa agt gaa aag cag aac cgg aaa caa ctg gaa ctc aag 2208 Ser LysPhe Lys Ser Glu Lys Gln Asn Arg Lys Gln Leu Glu Leu Lys 725 730 735 gtgaca tcc ctg gag gag gaa ctg act gac ctt cga gtt gag aag gag 2256 Val ThrSer Leu Glu Glu Glu Leu Thr Asp Leu Arg Val Glu Lys Glu 740 745 750 tccttg gaa aag aac ctc tca gaa agg aaa aag aag tca gct caa gag 2304 Ser LeuGlu Lys Asn Leu Ser Glu Arg Lys Lys Lys Ser Ala Gln Glu 755 760 765 cgttct cag gcc gag gag gag ata gat gaa att cgc aag tca tac cag 2352 Arg SerGln Ala Glu Glu Glu Ile Asp Glu Ile Arg Lys Ser Tyr Gln 770 775 780 gaggaa ttg gac aaa ctt cga cag ctc ttg aaa aag act cga gtg tcc 2400 Glu GluLeu Asp Lys Leu Arg Gln Leu Leu Lys Lys Thr Arg Val Ser 785 790 795 800aca gac caa gca gct gca gag cag ctg tct tta gta cag gct gag cta 2448 ThrAsp Gln Ala Ala Ala Glu Gln Leu Ser Leu Val Gln Ala Glu Leu 805 810 815cag acc cag tgg gaa gca aaa tgt gaa cat ttg ttg gcc tcc gcc aag 2496 GlnThr Gln Trp Glu Ala Lys Cys Glu His Leu Leu Ala Ser Ala Lys 820 825 830gat gag cac ctg cag cag tac cag gag gtg tgc gca cag aga gat gcc 2544 AspGlu His Leu Gln Gln Tyr Gln Glu Val Cys Ala Gln Arg Asp Ala 835 840 845tac cag cag aag ctg gta caa ctt cag gaa aag tgt tta gcc ctc cag 2592 TyrGln Gln Lys Leu Val Gln Leu Gln Glu Lys Cys Leu Ala Leu Gln 850 855 860gcc caa atc aca gct ctc acc aag caa aat gaa cag cac atc aag gaa 2640 AlaGln Ile Thr Ala Leu Thr Lys Gln Asn Glu Gln His Ile Lys Glu 865 870 875880 cta gag aag aac aag tcc cag atg tct ggg gtt gaa gct gct gca tct 2688Leu Glu Lys Asn Lys Ser Gln Met Ser Gly Val Glu Ala Ala Ala Ser 885 890895 gac ccc tca gag aag gtc aag aag atc atg aac cag gtg ttc cag tcc 2736Asp Pro Ser Glu Lys Val Lys Lys Ile Met Asn Gln Val Phe Gln Ser 900 905910 tta cgg aga gag ttt gag ctg gag gaa tct tac aat ggc agg acc att 2784Leu Arg Arg Glu Phe Glu Leu Glu Glu Ser Tyr Asn Gly Arg Thr Ile 915 920925 ctg gga acc atc atg aat acg atc aag atg gtg act ctt cag ctg tta 2832Leu Gly Thr Ile Met Asn Thr Ile Lys Met Val Thr Leu Gln Leu Leu 930 935940 aac caa cag gag caa gag aag gaa gag agc agc agt gaa gaa gaa gaa 2880Asn Gln Gln Glu Gln Glu Lys Glu Glu Ser Ser Ser Glu Glu Glu Glu 945 950955 960 gaa aaa gca gaa gag cgg cca cga aga cct tcc cag gag cag tca gcc2928 Glu Lys Ala Glu Glu Arg Pro Arg Arg Pro Ser Gln Glu Gln Ser Ala 965970 975 tca gcc agt tct ggg cag cct caa gca ccc ctg aat agg gag agg cca2976 Ser Ala Ser Ser Gly Gln Pro Gln Ala Pro Leu Asn Arg Glu Arg Pro 980985 990 gag tcc ccc atg gtg ccc tca gag cag gtg gtc gag gaa gct gtc ccg3024 Glu Ser Pro Met Val Pro Ser Glu Gln Val Val Glu Glu Ala Val Pro 9951000 1005 ttg cct cct cag gcc ctc acc act tcc cag gat gga cac aga aggaaa 3072 Leu Pro Pro Gln Ala Leu Thr Thr Ser Gln Asp Gly His Arg Arg Lys1010 1015 1020 ggg gac tca gaa gct gag gca ctc tca gag ata aaa gat ggttcc ctt 3120 Gly Asp Ser Glu Ala Glu Ala Leu Ser Glu Ile Lys Asp Gly SerLeu 1025 1030 1035 1040 cca ccc gaa ctg tct tgc atc cca tcc cac aga gttcta ggg ccc ccg 3168 Pro Pro Glu Leu Ser Cys Ile Pro Ser His Arg Val LeuGly Pro Pro 1045 1050 1055 act tca att cca cct gag ccc cta ggc cct gtatcc atg gac tct gag 3216 Thr Ser Ile Pro Pro Glu Pro Leu Gly Pro Val SerMet Asp Ser Glu 1060 1065 1070 tgt gag gag tca ctt gct gcc agc cca atggca gct aag ccc gac aac 3264 Cys Glu Glu Ser Leu Ala Ala Ser Pro Met AlaAla Lys Pro Asp Asn 1075 1080 1085 cca tca gga aag gtc tgt gtc agg gaagta gca cca gat ggc cca cta 3312 Pro Ser Gly Lys Val Cys Val Arg Glu ValAla Pro Asp Gly Pro Leu 1090 1095 1100 caa gaa agc tcc aca aga ctg tccctg act tca gac ccc gag gag ggg 3360 Gln Glu Ser Ser Thr Arg Leu Ser LeuThr Ser Asp Pro Glu Glu Gly 1105 1110 1115 1120 gac cca ctg gcc tta gggcct gaa agc cca gga gag cct cag cct cca 3408 Asp Pro Leu Ala Leu Gly ProGlu Ser Pro Gly Glu Pro Gln Pro Pro 1125 1130 1135 cag ctc aag aaa gatgat gtc act agc tcc acc ggt ccc cac aag gag 3456 Gln Leu Lys Lys Asp AspVal Thr Ser Ser Thr Gly Pro His Lys Glu 1140 1145 1150 ctg tca agc acagag gca ggt tcc aca gtt gca gga gca gcc ctc aga 3504 Leu Ser Ser Thr GluAla Gly Ser Thr Val Ala Gly Ala Ala Leu Arg 1155 1160 1165 ccc agc catcat tcc cag cgt tcc agt ctc tct ggg gat gaa gag gat 3552 Pro Ser His HisSer Gln Arg Ser Ser Leu Ser Gly Asp Glu Glu Asp 1170 1175 1180 gaa ctgttt aaa ggg gca act ctg aaa gct ctg agg ccc aaa gca cag 3600 Glu Leu PheLys Gly Ala Thr Leu Lys Ala Leu Arg Pro Lys Ala Gln 1185 1190 1195 1200cct gag gag gag gat gaa gac gag gtg agc atg aag gga cgc ccg ccc 3648 ProGlu Glu Glu Asp Glu Asp Glu Val Ser Met Lys Gly Arg Pro Pro 1205 12101215 cca acg ccc ctt ttt gga gat gat gat gat gac gat gac att gac tgg3696 Pro Thr Pro Leu Phe Gly Asp Asp Asp Asp Asp Asp Asp Ile Asp Trp1220 1225 1230 ctg gga tga agacccagga aactggtgca aaggtttctc tgcaaccctt3745 Leu Gly 1235 ccctaagcat gattttgcac agccaaccct gggtctaggc gagccacagggtgaggtcaa 3805 ggtgagcatt ctgggaacaa tatttgggct cagagggtgg gttggccaccttctgagccc 3865 cacccccgcc agacctggtg aagaggatca taaccctgtc ttcaagaacactgggatttc 3925 agcagcaagt tggaagaagg actggtaggt tcccctccaa gccagtcacctgtaagagtc 3985 ctgtcctctg ccagactttt taatctcttc attaactctc agactgacctgggagccctc 4045 ctctacctga atccagtgct caactgtgcc ccggcaacaa gacctgggctgaggtctccc 4105 tggtagaact aagggagatt acaccatcta aatcccagtg cagtcaacagcctggcctat 4165 agtcctggga catgtatctt cttctttgcc ttaaatctga tacaagaggtcaatgacttt 4225 gaaaataaaa ctaaaataaa tgtctataat gaaacttg 4263 6 1234PRT Homo sapiens 6 Gly Asn Thr Gln Leu Pro Pro Arg Asn Pro Val Lys AlaAsn Ala Met 1 5 10 15 Phe Gly Ala Gly Asp Glu Asp Asp Thr Asp Phe LeuSer Pro Ser Gly 20 25 30 Gly Ala Arg Leu Ala Ser Leu Phe Gly Leu Asp GlnAla Ala Ala Gly 35 40 45 His Gly Asn Glu Phe Phe Gln Tyr Thr Ala Pro LysGln Pro Lys Lys 50 55 60 Gly Gln Gly Thr Ala Ala Thr Gly Asn Gln Ala ThrPro Lys Thr Ala 65 70 75 80 Pro Ala Thr Met Ser Thr Pro Thr Ile Leu ValAla Thr Ala Val His 85 90 95 Ala Tyr Arg Tyr Thr Asn Gly Gln Tyr Val LysGln Gly Lys Phe Gly 100 105 110 Ala Ala Val Leu Gly Asn His Thr Ala ArgGlu Tyr Arg Ile Leu Leu 115 120 125 Tyr Ile Ser Gln Gln Gln Pro Val ThrVal Ala Arg Ile His Val Asn 130 135 140 Phe Glu Leu Met Val Arg Pro AsnAsn Tyr Ser Thr Phe Tyr Asp Asp 145 150 155 160 Gln Arg Gln Asn Trp SerIle Met Phe Glu Ser Glu Lys Ala Ala Val 165 170 175 Glu Phe Asn Lys GlnVal Cys Ile Ala Lys Cys Asn Ser Thr Ser Ser 180 185 190 Leu Asp Ala ValLeu Ser Gln Asp Leu Ile Val Ala Asp Gly Pro Ala 195 200 205 Val Glu ValGly Asp Ser Leu Glu Val Ala Tyr Thr Gly Trp Leu Phe 210 215 220 Gln AsnHis Val Leu Gly Gln Val Phe Asp Ser Thr Ala Asn Lys Asp 225 230 235 240Lys Leu Leu Arg Leu Lys Leu Gly Ser Gly Lys Val Ile Lys Gly Trp 245 250255 Glu Asp Gly Met Leu Gly Met Lys Lys Gly Gly Lys Arg Leu Leu Ile 260265 270 Val Pro Pro Ala Cys Ala Val Gly Ser Glu Gly Val Ile Gly Trp Thr275 280 285 Gln Ala Thr Asp Ser Ile Leu Val Phe Glu Val Glu Val Arg ArgVal 290 295 300 Lys Phe Ala Arg Asp Ser Gly Ser Asp Gly His Ser Val SerSer Arg 305 310 315 320 Asp Ser Ala Ala Pro Ser Pro Ile Pro Gly Ala AspAsn Leu Ser Ala 325 330 335 Asp Pro Val Val Ser Pro Pro Thr Ser Ile ProPhe Lys Ser Gly Glu 340 345 350 Pro Ala Leu Arg Thr Lys Ser Asn Ser LeuSer Glu Gln Leu Ala Ile 355 360 365 Asn Thr Ser Pro Asp Ala Val Lys AlaLys Leu Ile Ser Arg Met Ala 370 375 380 Lys Met Gly Gln Pro Met Leu ProIle Leu Pro Pro Gln Leu Asp Ser 385 390 395 400 Asn Asp Ser Glu Ile GluAsp Val Asn Thr Leu Gln Gly Gly Gly Gln 405 410 415 Pro Val Val Thr ProSer Val Gln Pro Ser Leu Gln Pro Ala His Pro 420 425 430 Ala Leu Pro GlnMet Thr Ser Gln Ala Pro Gln Pro Ser Val Thr Gly 435 440 445 Leu Gln AlaPro Ser Ala Ala Leu Met Gln Val Ser Ser Leu Asp Ser 450 455 460 His SerAla Val Ser Gly Asn Ala Gln Ser Phe Gln Pro Tyr Ala Gly 465 470 475 480Met Gln Ala Tyr Ala Tyr Pro Gln Ala Ser Ala Val Thr Ser Gln Leu 485 490495 Gln Pro Val Arg Pro Leu Tyr Pro Ala Pro Leu Ser Gln Pro Pro His 500505 510 Phe Gln Gly Ser Gly Asp Met Ala Ser Phe Leu Met Thr Glu Ala Arg515 520 525 Gln His Asn Thr Glu Ile Arg Met Ala Val Ser Lys Val Ala AspLys 530 535 540 Met Asp His Leu Met Thr Lys Val Glu Glu Leu Gln Lys HisSer Ala 545 550 555 560 Gly Asn Ser Met Leu Ile Pro Ser Met Ser Val ThrMet Glu Thr Ser 565 570 575 Met Ile Met Ser Asn Ile Gln Arg Ile Ile GlnGlu Asn Glu Arg Leu 580 585 590 Lys Gln Glu Ile Leu Glu Lys Ser Asn ArgIle Glu Glu Gln Asn Asp 595 600 605 Lys Ile Ser Glu Leu Ile Glu Arg AsnGln Arg Tyr Val Glu Gln Ser 610 615 620 Asn Leu Met Met Glu Lys Arg AsnAsn Ser Leu Gln Thr Ala Thr Glu 625 630 635 640 Asn Thr Gln Ala Arg ValLeu His Ala Glu Gln Glu Lys Ala Lys Val 645 650 655 Thr Glu Glu Leu AlaAla Ala Thr Ala Gln Val Ser His Leu Gln Leu 660 665 670 Lys Met Thr AlaHis Gln Lys Lys Glu Thr Glu Leu Gln Met Gln Leu 675 680 685 Thr Glu SerLeu Lys Glu Thr Asp Leu Leu Arg Gly Gln Leu Thr Lys 690 695 700 Val GlnAla Lys Leu Ser Glu Leu Gln Glu Thr Ser Glu Gln Ala Gln 705 710 715 720Ser Lys Phe Lys Ser Glu Lys Gln Asn Arg Lys Gln Leu Glu Leu Lys 725 730735 Val Thr Ser Leu Glu Glu Glu Leu Thr Asp Leu Arg Val Glu Lys Glu 740745 750 Ser Leu Glu Lys Asn Leu Ser Glu Arg Lys Lys Lys Ser Ala Gln Glu755 760 765 Arg Ser Gln Ala Glu Glu Glu Ile Asp Glu Ile Arg Lys Ser TyrGln 770 775 780 Glu Glu Leu Asp Lys Leu Arg Gln Leu Leu Lys Lys Thr ArgVal Ser 785 790 795 800 Thr Asp Gln Ala Ala Ala Glu Gln Leu Ser Leu ValGln Ala Glu Leu 805 810 815 Gln Thr Gln Trp Glu Ala Lys Cys Glu His LeuLeu Ala Ser Ala Lys 820 825 830 Asp Glu His Leu Gln Gln Tyr Gln Glu ValCys Ala Gln Arg Asp Ala 835 840 845 Tyr Gln Gln Lys Leu Val Gln Leu GlnGlu Lys Cys Leu Ala Leu Gln 850 855 860 Ala Gln Ile Thr Ala Leu Thr LysGln Asn Glu Gln His Ile Lys Glu 865 870 875 880 Leu Glu Lys Asn Lys SerGln Met Ser Gly Val Glu Ala Ala Ala Ser 885 890 895 Asp Pro Ser Glu LysVal Lys Lys Ile Met Asn Gln Val Phe Gln Ser 900 905 910 Leu Arg Arg GluPhe Glu Leu Glu Glu Ser Tyr Asn Gly Arg Thr Ile 915 920 925 Leu Gly ThrIle Met Asn Thr Ile Lys Met Val Thr Leu Gln Leu Leu 930 935 940 Asn GlnGln Glu Gln Glu Lys Glu Glu Ser Ser Ser Glu Glu Glu Glu 945 950 955 960Glu Lys Ala Glu Glu Arg Pro Arg Arg Pro Ser Gln Glu Gln Ser Ala 965 970975 Ser Ala Ser Ser Gly Gln Pro Gln Ala Pro Leu Asn Arg Glu Arg Pro 980985 990 Glu Ser Pro Met Val Pro Ser Glu Gln Val Val Glu Glu Ala Val Pro995 1000 1005 Leu Pro Pro Gln Ala Leu Thr Thr Ser Gln Asp Gly His ArgArg Lys 1010 1015 1020 Gly Asp Ser Glu Ala Glu Ala Leu Ser Glu Ile LysAsp Gly Ser Leu 1025 1030 1035 1040 Pro Pro Glu Leu Ser Cys Ile Pro SerHis Arg Val Leu Gly Pro Pro 1045 1050 1055 Thr Ser Ile Pro Pro Glu ProLeu Gly Pro Val Ser Met Asp Ser Glu 1060 1065 1070 Cys Glu Glu Ser LeuAla Ala Ser Pro Met Ala Ala Lys Pro Asp Asn 1075 1080 1085 Pro Ser GlyLys Val Cys Val Arg Glu Val Ala Pro Asp Gly Pro Leu 1090 1095 1100 GlnGlu Ser Ser Thr Arg Leu Ser Leu Thr Ser Asp Pro Glu Glu Gly 1105 11101115 1120 Asp Pro Leu Ala Leu Gly Pro Glu Ser Pro Gly Glu Pro Gln ProPro 1125 1130 1135 Gln Leu Lys Lys Asp Asp Val Thr Ser Ser Thr Gly ProHis Lys Glu 1140 1145 1150 Leu Ser Ser Thr Glu Ala Gly Ser Thr Val AlaGly Ala Ala Leu Arg 1155 1160 1165 Pro Ser His His Ser Gln Arg Ser SerLeu Ser Gly Asp Glu Glu Asp 1170 1175 1180 Glu Leu Phe Lys Gly Ala ThrLeu Lys Ala Leu Arg Pro Lys Ala Gln 1185 1190 1195 1200 Pro Glu Glu GluAsp Glu Asp Glu Val Ser Met Lys Gly Arg Pro Pro 1205 1210 1215 Pro ThrPro Leu Phe Gly Asp Asp Asp Asp Asp Asp Asp Ile Asp Trp 1220 1225 1230Leu Gly 7 690 DNA Homo sapiens CDS (1)..(555) 7 atg ggg gcg ctg ctg ctggag aag gaa acc aga gga gcc acc gag aga 48 Met Gly Ala Leu Leu Leu GluLys Glu Thr Arg Gly Ala Thr Glu Arg 1 5 10 15 gtt cat ggc tct ttg ggggac acc cct cgt agt gaa gaa acc ctg ccc 96 Val His Gly Ser Leu Gly AspThr Pro Arg Ser Glu Glu Thr Leu Pro 20 25 30 aag gcc acc ccc gac tcc ctggag cct gct ggc ccc tca tct cca gcc 144 Lys Ala Thr Pro Asp Ser Leu GluPro Ala Gly Pro Ser Ser Pro Ala 35 40 45 tct gtc act gtc act gtt ggt gatgag ggg gct gac acc cct gta ggg 192 Ser Val Thr Val Thr Val Gly Asp GluGly Ala Asp Thr Pro Val Gly 50 55 60 gct aca cca ctc att ggg gat gaa tctgag aat ctt gag gga gat ggg 240 Ala Thr Pro Leu Ile Gly Asp Glu Ser GluAsn Leu Glu Gly Asp Gly 65 70 75 80 gac ctc cgt ggg ggc cgg atc ctg ctgggc cat gcc aca aag tca ttc 288 Asp Leu Arg Gly Gly Arg Ile Leu Leu GlyHis Ala Thr Lys Ser Phe 85 90 95 ccc tct tcc ccc agc aag ggg ggt tcc tgtcct agc cgg gcc aag atg 336 Pro Ser Ser Pro Ser Lys Gly Gly Ser Cys ProSer Arg Ala Lys Met 100 105 110 tca atg aca ggg gcg gga aaa tca cct ccatct gtc cag agt ttg gct 384 Ser Met Thr Gly Ala Gly Lys Ser Pro Pro SerVal Gln Ser Leu Ala 115 120 125 atg agg cta ctg agt atg cca gga gcc caggga gct gca gca gca ggg 432 Met Arg Leu Leu Ser Met Pro Gly Ala Gln GlyAla Ala Ala Ala Gly 130 135 140 tct gaa ccc cct cca gcc acc acg agc ccagag gga cag ccc aag gtc 480 Ser Glu Pro Pro Pro Ala Thr Thr Ser Pro GluGly Gln Pro Lys Val 145 150 155 160 cac cga gcc cgc aaa acc atg tcc aaacca gga aat gga cag cat acc 528 His Arg Ala Arg Lys Thr Met Ser Lys ProGly Asn Gly Gln His Thr 165 170 175 aag acc cca tct cta aaa gaa gtt taaaagaatgttt caaaggccag 575 Lys Thr Pro Ser Leu Lys Glu Val 180 185gcccagtgac tcacgcctgt aatcccgtac tttctgggga ggatcacttg acaccaggag 635ttcaagacca gcctgggcaa catggcaaga cctcttctct accaaaaaaa aaaat 690 8 184PRT Homo sapiens 8 Met Gly Ala Leu Leu Leu Glu Lys Glu Thr Arg Gly AlaThr Glu Arg 1 5 10 15 Val His Gly Ser Leu Gly Asp Thr Pro Arg Ser GluGlu Thr Leu Pro 20 25 30 Lys Ala Thr Pro Asp Ser Leu Glu Pro Ala Gly ProSer Ser Pro Ala 35 40 45 Ser Val Thr Val Thr Val Gly Asp Glu Gly Ala AspThr Pro Val Gly 50 55 60 Ala Thr Pro Leu Ile Gly Asp Glu Ser Glu Asn LeuGlu Gly Asp Gly 65 70 75 80 Asp Leu Arg Gly Gly Arg Ile Leu Leu Gly HisAla Thr Lys Ser Phe 85 90 95 Pro Ser Ser Pro Ser Lys Gly Gly Ser Cys ProSer Arg Ala Lys Met 100 105 110 Ser Met Thr Gly Ala Gly Lys Ser Pro ProSer Val Gln Ser Leu Ala 115 120 125 Met Arg Leu Leu Ser Met Pro Gly AlaGln Gly Ala Ala Ala Ala Gly 130 135 140 Ser Glu Pro Pro Pro Ala Thr ThrSer Pro Glu Gly Gln Pro Lys Val 145 150 155 160 His Arg Ala Arg Lys ThrMet Ser Lys Pro Gly Asn Gly Gln His Thr 165 170 175 Lys Thr Pro Ser LeuLys Glu Val 180

1. An isolated polypeptide comprising (i) the amino acid sequence of anyone of SEQ ID NO. 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8; (ii) avariant thereof having substantially similar function selected fromimmunomodulatory activity and/or anti-viral activity and/or anti-tumouractivity; or (iii) a fragment of a sequence as defined in (i) or (ii)which retains substantially similar function selected fromimmunomodulatory activity and/or anti-viral activity and/or anti-tumouractivity for use in therapeutic treatment of a human or non-humananimal.
 2. An isolated polynucleotide which directs expression in vivoof a polypeptide as defined in claim 1 for use in therapeutic treatmentof a human or non-human animal.
 3. An isolated polynucleotide as claimedin claim 2 which includes a sequence comprising: (a) the nucleic acid ofSEQ ID NO: 1, SEQ ID NO:
 3. SEQ ID NO: 5 or SEQ ID NO: 7 or the codingsequence thereof; (b) a sequence which hybridises to a sequencecomplementary to a sequence as defined in (a); (c) a sequence which isdegenerate as a result of the genetic code to a sequence as defined in(a) or (b); or (d) a sequence having at least 60% identity to a sequenceas defined in (a), (b) or (c); such that the polypeptide encoded by saidsequence is capable of expression in vivo.
 4. A polypeptide orpolynucleotide as claimed in any one of claims 1 to 3 for use as ananti-viral, anti-tumour or immunomodulatory agent.
 5. A polypeptide orpolynucleotide as claimed in claim 4 for use in treating a Type 1interferon treatable disease.
 6. A pharmaceutical composition comprisinga polypeptide or polynucleotide as claimed in any one of claims 1 to 5and a pharmaceutically acceptable carrier or diluent.
 7. Use of apolypeptide or polynucleotide as defined in any one of claims 1 to 5 inthe preparation of a medicament for use in therapy as an anti-viral,anti-tumour or immunomodulatory agent.
 8. A method of treating a patienthaving a Type 1 interferon treatable disease, which comprisesadministering to said patient an effective amount of a polypeptide orpolynucleotide as defined in any one of claims 1 to
 5. 9. A method ofpredicting responsiveness of a patient to treatment with a Type 1interferon, which comprises determining the level of one or moreproteins selected from the proteins defined by the sequences set forthin SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8 andnaturally-occurring variants thereof, or one or more of thecorresponding mRNAs, in a cell sample from said patient, wherein saidsample is obtained from said patient following administration of a Type1 interferon or is treated prior to said determining with a Type 1interferon in vitro.
 10. A method as claimed in claim 9 wherein theinterferon administered prior to obtaining said sample or used to treatsaid sample in vitro is the interferon proposed for treatment.
 11. Amethod as claimed in claim 9 or 10 wherein a sample comprisingperipheral blood mononuclear cells isolated from a blood sample of thepatient is treated with a Type 1 interferon in vitro.
 12. A method asclaimed in any one of claims 9 to 11 wherein said determining comprisesdetermining the level of mRNA encoding the protein defined by thesequence set forth in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ IDNO: 8 or a naturally-occurring variant of said protein.
 13. Apolynucleotide capable of expressing in vivo an antisense sequence to acoding sequence for the amino acid sequence defined by SEQ ID NO: 2, SEQID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8or a naturally-occurring variantof said coding sequence for use in therapeutic treatment of a human ornon-human animal.
 14. An antibody to the amino acid sequence set forthin SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8 for use intherapeutic treatment of a human or animal body.